F O C U S O N M E TA B O L I S M A N D I M MU N O LO G Y

REVIEWS


  
Abstract | The worldwide epidemic of obesity has brought considerable attention to
research aimed at understanding the biology of adipocytes (fat cells) and the events
occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating
evidence indicates that obesity causes chronic low-grade inflammation and that this
contributes to systemic metabolic dysfunction that is associated with obesity-linked
disorders. Adipose tissue functions as a key endocrine organ by releasing multiple
bioactive substances, known as adipose-derived secreted factors or adipokines, that
have pro-inflammatory or anti-inflammatory activities. Dysregulated production or
secretion of these adipokines owing to adipose tissue dysfunction can contribute to
the pathogenesis of obesity-linked complications. In this Review, we focus on the
role of adipokines in inflammatory responses and discuss their potential as regulators
of metabolic function.

 Obesity and inflammation


   
        
   

 


 
 
   
 
 
 
  
  
 
  
  


  
   
  
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  

  

 
   
  
  


 
  
  

  IMMUNOLO GY        85


REVIEWS

 


 

















Figure 1 | Adipose tissue depots. Adipose tissue is mainly found in subcutaneous

and visceral depots. Under conditions of obesity, adipose tissue expands in these and
other depots throughout the body. Common sites of adipose tissue accumulation
include the heart, the kidneys and the adventitia of blood vessels. Differential  
adipokine secretion by various adipose tissue depots may selectively affect organ 
function and systemic metabolism. 

  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 

   
 
 
 
 
 
 
  
 
   
 
 
  
  
 
 
   

86       www.nature.com/reviews/immunol


 F O C U S O N M E TA B O L I S M A N D I M MURNEOVLO
IEWGY
S

Table 1 | Sources and functions of key adipokines

Adipokine Primary source(s) Binding partner or receptor Function
Leptin Adipocytes Leptin receptor Appetite control through the
central nervous system
Resistin Peripheral blood mononuclear Unknown Promotes insulin resistance and
cells (human), adipocytes inflammation through IL-6 and
(rodent) TNF secretion from macrophages
RBP4 Liver, adipocytes, macrophages Retinol (vitamin A), Implicated in systemic insulin
transthyretin resistance
Lipocalin 2 Adipocytes, macrophages Unknown Promotes insulin resistance
and inflammation through TNF
secretion from adipocytes
ANGPTL2 Adipocytes, other cells Unknown Local and vascular inflammation
TNF Stromal vascular fraction cells, TNF receptor Inflammation, antagonism of
adipocytes insulin signalling
IL-6 Adipocytes, stromal vascular IL-6 receptor Changes with source and target
fraction cells, liver, muscle tissue
IL-18 Stromal vascular fraction cells IL-18 receptor, IL-18 binding Broad-spectrum inflammation
protein
CCL2 Adipocytes, stromal vascular CCR2 Monocyte recruitment
fraction cells
CXCL5 Stromal vascular fraction cells CXCR2 Antagonism of insulin signalling
(macrophages) through the JAK–STAT pathway
NAMPT Adipocytes, macrophages, Unknown Monocyte chemotactic activity
other cells
Adiponectin Adipocytes Adiponectin receptors 1 and 2, Insulin sensitizer,
T cadherin, calreticulin–CD91
T- anti-inflammatory
SFRP5 Adipocytes WNT5a Suppression of pro-inflammatory
WNT signalling
ANGPTL2, angiopoietin-like protein 2; CCL2, CC-chemokine ligand 2; CXCL5, CXC-chemokine ligand 5; IL, interleukin; JAK, Janus
kinase; NAMPT, nicotinamide phosphoribosyltransferase; RBP4, retinol-binding protein 4; SFRP5, secreted frizzled-related protein 5;
STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.

 
  
  
  
  


 
  
    
  

 
  
  
  
   

 
 
  
  
  

 
  
  
  
  


 
  
   

  IMMUNOLO GY        87


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






 





 

Pro-inflammatory adipokines


 



 
 




Figure 2 | Components of adipose tissue. a | Adipocytes are the main cellular

component of adipose tissue, and they are crucial for both energy storage and
endocrine activity. The other cell types that are present are precursor cells (including 
pre-adipocytes), fibroblasts, vascular cells and immune cells, and these cells constitute the 
stromal vascular fraction of adipose tissue. Vascular cells include both endothelial cells 
and vascular smooth muscle cells, which are associated with the major blood vessels. The 
blood vessels in adipose tissue are required for the proper flow of nutrients and oxygen
to adipocytes, and they are the conduits that allow for the distribution of adipokines. 
Vascular cells also secrete, and are responsive to, adipose tissue-secreted proteins. 
Other active adipose tissue components include macrophages and T cells, which have  
major roles in determining the immune status of adipose tissue. The fibroblast-derived 
extracellular matrix functions to provide mechanical support, and excess matrix can

lead to adipose tissue dysfunction. Factors that are secreted by these different cellular
components are critical for maintaining homeostasis in adipose tissue and throughout 
the body. b | Examples of intercellular communication between different adipose tissue 
cell types include the counter-regulation between adiponectin and tumour necrosis   
factor (TNF), and between secreted frizzled-related protein 5 (SFRP5) and WNT5a. 
Under conditions of obesity the pro-inflammatory factors (TNF and WNT5a) predominate. 



 
 
  
 
 
  
 
 
   
 
 
      
      
 
 

88       www.nature.com/reviews/immunol


 F O C U S O N M E TA B O L I S M A N D I M MURNEOVLO
IEWGY
S

Box 1 | Vascular function in adipose tissue   

     
Recent interest has been paid to the status of the vasculature in adipose tissue. It has 
been shown that obesity can lead to capillary rarefaction in adipose tissue leading to  
146,147
localized hypoxia . Theoretically, reductions in blood flow in obese adipose tissue

could limit the delivery of nutrients, thereby contributing to insulin resistance.

Perhaps more importantly, a restriction of blood flow in adipose tissue could contribute
to an inflammatory state, possibly as a result of ischaemia-induced adipocyte necrosis 
and the subsequent recruitment of macrophages. Furthermore, obesity leads to the  
downregulation of anti-inflammatory factors, such as adiponectin, that pacify the 
vascular endothelium, and the upregulation of pro-inflammatory factors that activate 
11
endothelial cells and promote a dysfunctional phenotype . In turn, the activated     
vascular endothelium expresses adhesion molecules and chemotactic factors that 

accelerate and localize inflammatory processes. Thus, the status of endothelial cell 
function may have an integral role both in mediating the effects of metabolic disease on 
the cardiovascular system and in controlling the metabolic state of the organism by

influencing, either positively or negatively, the microenvironment in adipose tissue.

Therefore, it can be posited that obesity favours a vicious cycle whereby endothelial cell 
dysfunction in the adipose tissue leads to metabolic dysfunction, reflected by 
 
120
adipokine dysregulation, adipocyte necrosis and inflammation . In turn, metabolic 
dysfunction promotes endothelial cell dysfunction, both in the adipose tissue and 

systemic circulation, putting further stress on adipocytes. However, in contrast to these      
considerations, it has been reported that obese mice receiving anti-angiogenic reagents   
have a reduced body weight and adipose mass, and show increased metabolic rates148.  
Because there is a close interplay between adipogenesis and angiogenesis in obesity149, 
further analysis of the role of adipokines in controlling vascular growth and metabolic  
function during adipose tissue expansion should be of interest.



  
 
  
 

  
  
  
   
   
 
   
  
 
  
  
          
 
 
  
  
    


 
  
  
  

 

    
  
   
   
   


 
  
    

  IMMUNOLO GY        89


REVIEWS

Figure 3 | Phenotypic modulation of adipose tissue. Adipose tissue can be described by at least three structural and
functional classifications: lean with normal metabolic function, obese with mild metabolic dysfunction and obese with full
metabolic dysfunction. As obesity develops, adipocytes undergo hypertrophy owing to increased triglyceride storage. With
limited obesity, it is likely that the tissue retains relatively normal metabolic function and has low levels of immune cell activation
and sufficient vascular function. However, qualitative changes in the expanding adipose tissue can promote the transition to a
metabolically dysfunctional phenotype. Macrophages in lean adipose tissue express markers of an M2 or alternatively activated
state, whereas obesity leads to the recruitment and accumulation of M1 or classically activated macrophages, as well as T cells,
in adipose tissue. Anti-inflammatory adipokines, including adiponectin and secreted frizzled-related protein 5 (SFRP5), are
preferentially produced by lean adipose tissue. In states of obesity, adipose tissue generates large amounts of pro-inflammatory
factors, including leptin, resistin, retinol-binding protein 4 (RBP4), lipocalin 2, angiopoietin-like protein 2 (ANGPTL2), tumour
necrosis factor (TNF), interleukin-6 (IL-6), IL-18, CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 5 (CXCL5) and
nicotinamide phosphoribosyltransferase (NAMPT). Obese individuals with adipose tissue in a metabolically intermediate state
have improved metabolic parameters, diminished inflammatory marker expression and better vascular function compared with
individuals that have metabolically dysfunctional adipose tissue. Metabolically dysfunctional adipose tissue can be associated
with higher levels of adipocyte necrosis, and M1 macrophages are arranged around these dead cells in crown-like structures.

 
  
   
 
 
 
 
 
 
 
  
    
  
 
  
 
  
 
 
  
 
  
 
 
       

90       www.nature.com/reviews/immunol


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 
 
 
 
   
 
 
 
 

 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
  
 
 

   
  
 
 
  
        
      
 
 
 
  
  

 
 
 
 
 
 
  
  
   
 
   

  
  
  
  


 
   
   

  IMMUNOLO GY        91


REVIEWS

 
 
 
 
  
 
 

 
 
  

 
  
 
        
 
 
  
 
  

      
 
 
  
 
    
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
  
  
Anti-inflammatory adipokines 
 
 
  
  
 
 

 
 

  
 
 
 
 
 
         

92       www.nature.com/reviews/immunol


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 
 
 
   
 
 
 
 
 
  
  


   
 
 
 
 
 
 

 
 
  
 
 
 
 
 
 
 
  
 

Box 2 | Cardiovascular effects of adiponectin

Clinical studies have identified an association between low serum levels of adiponectin and coronary artery disease150,
hypertension151, left ventricular hypertrophy152 and a greater risk of myocardial infarction153. Early experimental studies
showed that adiponectin reduces tumour necrosis factor (TNF)-stimulated expression of interleukin-8 (IL-8) and vascular
endothelial cell adhesion molecules (such as vascular cell adhesion molecule 1 (VCAM1)) through the suppression of nuclear
factor- B (NF- B) activation, and thus diminishes monocyte attachment154–156. Consistent with these in vitro findings,
overexpression of adiponectin inhibits the formation of atherosclerotic lesions and decreases the expression of class A
scavenger receptors (SR-A), TNF and VCAM1 in the aorta in a model of atherosclerosis157,158, whereas the ablation of
adiponectin leads to augmented atherosclerosis that is associated with increased T cell accumulation in atheratoma159.
However, a recent study did not find an association between atherosclerosis and levels of circulating adiponectin, such that
in a low-density lipoprotein receptor (LDLR)-deficient mouse model, atherosclerosis was not altered in states of adiponectin
deficiency or chronic overexpression160. Related studies have shown that adiponectin also promotes vascular homeostasis
through its ability to activate endothelial nitric oxide synthase (eNOS), a key determinant of endothelial cell function.
Adiponectin promotes eNOS activation in endothelial cells through AMP-activated protein kinase (AMPK)-dependent
phosphorylation of this enzyme161,162. In addition, adiponectin stimulates endothelial cell migration and differentiation
to form capillary-like structures, and prevents endothelial cell apoptosis through activation of AMPK signalling161–163.
In keeping with these in vitro observations, adiponectin-deficient mice develop hypertension and impaired endothelial
cell-dependent vasodilation when fed an atherogenic diet164. Disruption of adiponectin also leads to the enhancement
of salt-induced hypertension and the reduction of eNOS expression in the aorta165. Adiponectin suppresses cerebral
ischaemia–reperfusion injury166 and promotes the revascularization response to chronic hindlimb ischaemia through
activation of the AMPK–eNOS signalling pathway167,168. Finally, recent evidence has shown that adiponectin also promotes
the expression of the autacoid prostaglandin I2 (PGI2) by endothelial cells, contributing to the improved vascular function
that is attributed to this adipokine169. Adiponectin also inhibits pathological cardiac remodelling following pressure
 overload or angiotensin II infusion in vivo, at least in part through its ability to activate AMPK signalling in myocytes170,171.
 Adiponectin protects the heart from detrimental remodelling (such as fibrosis) and heart failure after myocardial
 infarction172, and a recent study has shown that aldosterone-infused adiponectin-deficient mice show exacerbated
 diastolic dysfunction173. Of particular interest, the glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein

T cadherin has been shown to be required for localizing adiponectin to the lumenal surface of the vascular endothelium174
T-

and for conferring the cardioprotective action of adiponectin175. Overall, adiponectin is a protective adipokine against


the development of obesity-linked heart diseases, and it is a molecular link between adipose and cardiovascular tissues.

  IMMUNOLO GY        93


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 
 
 
 
 
 
 
 
  
 
        
  
 
 
 
   
 
 
   
 
 
 
 
 
 
 

 
 
 

 
 
 
 
 
 
  

 Concluding remarks
 
 
 
 
  
 
 


Box 3 | Adiponectin and inflammatory lung disease 

A baseline phenotype of adiponectin-deficient mice is emphysema-like dilated

airspaces and alveolar macrophage activation176. In addition, adiponectin-deficient
mice develop a pulmonary hypertension phenotype that is associated with perivascular 
inflammation177,178. Obesity is a risk factor for the development of asthma, and 
micro-pump administration of recombinant adiponectin is reported to reduce allergic 
lung inflammation in an asthma model of ovalbumin sensitization and challenge179. Little 
is known about the mechanisms by which adiponectin suppresses inflammation in the 
lungs. Adiponectin receptor 1 is expressed by lung epithelial cells180, and T
T-cadherin 
seems to be required to facilitate the entry of adiponectin into the lungs181. Whereas 
expression of adiponectin is reduced in subjects who smoke cigarettes, increased levels 
are found in those with chronic obstructive pulmonary disease180 and high levels of

adiponectin are associated with mortality in patients with respiratory failure182.


94       www.nature.com/reviews/immunol


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     

   
       
      
    
      
      
      
  
         
     
 
    
      
      
   
       
       
       
    
    
    
     
    
     
     
   
      
      
        
     
  
        
     
         
  
         
    
   
    
        
   
      
     
    
     
      
       
   
   
   
      
     
       
    
      
   
    
    
       
    
   
          
    
     
    
      
   
    
      
    
     
     
    
    
      
    
     
   
       
      
        
    
      
    
    
    
  
     
    
       
   

  IMMUNOLO GY        95


REVIEWS

         
  
     
   
           
   
       
    
      
  
      
       
      
   
     
      
     
     
     
     
        
      
      
      
    
  
     
      
     
     
    
     
        
       
     
     
       
     
    
   
    
     
      
    
  
      
  
         
     
   
        
  
       
  
     
     
   
     
    
   
    
      
   
  
       
  
         
   
    
        
        
   
    
         
     
  
      
   
        
   
          
    
     
     
       
      
     
    
  
    
  

96       www.nature.com/reviews/immunol


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        

  
   
           
    
    
    
   
        
    
  
       
    
   
    
        
   
    
      
     
   
  
        
    
  
   
    
       
     
    
        
   
   
   
   
         
  
    
    
       
   
  
     
       
     
    
      
      
   
   
      
   
    
    
      
       
     
    
    
   

  

  

   
   
   
   

  IMMUNOLO GY        97

