Progress in Cardiovascular Diseases 62 (2019) 327–333

Contents lists available at ScienceDirect

Progress in Cardiovascular Diseases

journal homepage: www.onlinepcd.com

Review

Obesity, risk of diabetes and role of physical activity, exercise training and
cardiorespiratory fitness
Salvatore Carbone a,b,⁎, Marco Giuseppe Del Buono c, Cemal Ozemek d, Carl J. Lavie e
a
Department of Kinesiology & Health Sciences, College of Humanities & Sciences, Virginia Commonwealth University, Richmond, VA, United States of America
b
VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States of America
c
Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Rome, Italy
d
Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, United States of America
e
Department of Cardiovascular Disease, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, the University of Queensland School of Medicine, New Orleans, LA, United States of America

a r t i c l e i n f o a b s t r a c t

Article history: The epidemic of obesity contributes to the burden of type 2 diabetes mellitus (T2DM) in the United States and
Received 14 August 2019 worldwide. Importantly, obesity is not only preventable but can be treated, particularly with lifestyle modifica-
Accepted 14 August 2019 tions to forestall T2DM in those with excess adiposity. The mechanisms linking obesity to T2DM are numerous
and involve adipose tissue remodeling as a result of unhealthy behaviors, including unhealthy diet, reduced phys-
ical activity (PA) and exercise training (ET), and increased sedentary behaviors. Taken together, these factors
Keywords:
Obesity
markedly reduce cardiorespiratory fitness (CRF), one of the strongest predictors for cardiovascular outcomes
Diabetes and all-cause mortality in the general population, but also in those with T2DM.
Cardiorespiratory fitness In this review we describe the mechanisms leading to adipose tissue remodeling resulting in obesity, as well as
Physical activity the mechanisms linking excess adiposity to insulin resistance and, in turn, T2DM. We then present the therapeu-
Exercise training tic strategies that can be implemented in obesity to prevent T2DM, with a brief discussion on weight loss, and
Sedentary behaviors greater emphasis on PA and ET. We finally present the evidence to support the beneficial effects of such strategies
in patients with established T2DM and discuss the importance of achieving improvements in CRF in this popula-
tion to potentially improve clinical outcomes.
© 2019 Elsevier Inc. All rights reserved.

Contents

Obesity and adipose tissue remodeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

Mechanisms leading obesity to T2DM: contributions of insulin resistance and chronic low-grade systemic inflammation. . . . . . . . . . . . . . . . 328
PA and ET to improve body weight and CRF to prevent T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
PA and ET to increase CRF in T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Funding support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Abbreviations: ADA, American Diabetes Association; BMI, body mass index; CRF, car- Overweight and obesity are defined as excess adiposity that impairs
diorespiratory fitness; CV, cardiovascular; CVD, cardiovascular disease; DPP, Diabetes health,1 and together they affect over two thirds of the population in the
Prevention Program; ET, exercise training; FFA, free-fatty acids; FM, fat mass; GLUT4,
United States, with obesity alone having a prevalence of 39.6% (41.1% in
glucose-transporter type 4; HbA1c, glycated hemoglobin; IL, interleukin; MET, metabolic
equivalent of tasks; NLRP3, Nod-like receptor pyrin domain-containing protein; PA, phys- women and 37.9% in men), and severe obesity of 7.7% (9.7% in women
ical activity; SB, sedentary behavior; T2DM, type 2 diabetes mellitus; VO2, oxygen con- and 5.6% in men).2 The observed increase of obesity in the last decades
sumption; WC, waist circumference. is concerning due to the increased metabolic and cardiovascular (CV)
⁎ Corresponding author at: Department of Kinesiology & Health Sciences, College of disease (CVD) risk associated with the increased adiposity,3 resulting
Humanities & Sciences, Virginia Commonwealth University, 500 Academic Centre, Room
113c, 1020 W Grace Street, P.O. Box 843021, Richmond, VA, 23220, United States of
in unacceptably high healthcare costs and reduced quality of life.3,4
America. Obesity is highly associated with perturbation of glucose metabo-
E-mail address: salvatore.carbone@vcuhealth.org (S. Carbone). lism, resulting in the development of type 2 diabetes mellitus

https://doi.org/10.1016/j.pcad.2019.08.004
0033-0620/© 2019 Elsevier Inc. All rights reserved.
328 S. Carbone et al. / Progress in Cardiovascular Diseases 62 (2019) 327–333

(T2DM).5,6 Importantly, several non-pharmacologic, pharmacologic and adipocytes. Of note, therapies aimed at reducing body fat, such as caloric
surgical interventions are effective in preventing the development of restriction, are associated with an improvement in adipocytes hypertro-
T2DM in overweight or obese individuals, highlighting the importance phy, but not of hyperplasia, making weight regain more likely to occur if
of early interventions in this population. Obesity alone, even in absence energy balance returns to a positive state.22 Additionally, adipocytes can
of T2DM, strongly associates with greater CVD risk, and reducing excess be divided into subtypes, based on their color, from white to brown,
adipose tissue serves as a therapeutic means to prevent the develop- with a more recently proposed brown-like beige adipocyte, with char-
ment of CVD.3 Of note, both obesity and T2DM are associated with a sig- acteristics of both white and brown adipose tissue.26 The distinction be-
nificant reduction in cardiorespiratory fitness (CRF).7,8 Considering that tween white and brown adipose tissue is of utmost importance,
greater CRF is associated with overall improved survival, therapies particularly after the discovery a decade ago of active brown adipose tis-
aimed at increasing CRF, such as increased physical activity (PA), exer- sue in adult humans.27 While white adipocytes are considered the most
cise training (ET) and potentially reduced sedentary behaviors (SB), common adipocytes responsible for the expansion of the adipose tissue
have been proposed as therapeutic strategies.9–11 (both visceral and subcutaneous), brown adipocytes are present in very
In this review we will describe the role of obesity, and particularly of small amounts, and their most well-known role is their ability to control
body composition (i.e., fat mass [FM]), on the risk for T2DM. We will thermogenesis.28 As such, therapeutics currently under investigation
also discuss the non-pharmacologic interventions, with a focus on life- are aimed at increasing brown adipose tissue amount or activity, or
style modifications (i.e., diet, PA and ET) to prevent and treat the several beigeing of white adipose tissue, and simulating its effects to increase
cardiometabolic abnormalities associated with obesity and T2DM. daily energy expenditure, even in absence of increased PA, to promote
a greater energy deficit to treat obesity and prevent the obesity-
Obesity and adipose tissue remodeling related metabolic abnormalities.29–32

Obesity is a multifactorial chronic disease, in which environmental Mechanisms leading obesity to T2DM: contributions of insulin resis-
and genetic factors, as well as abnormalities of energy metabolism reg- tance and chronic low-grade systemic inflammation
ulation, which may be caused by the use of medications that induce
weight gain as a side effect, contribute to weight gain. Monogenic With respect to the risk of metabolic diseases, obesity remains per-
forms of obesity, mainly resulting from dysregulation of energy homeo- haps the strongest modifiable risk factor for the development of insulin
stasis, also exist.12 Although environmental factors (i.e., unhealthy diet, resistance, ultimately resulting in T2DM.33 Hyperplasia and hypertro-
physical inactivity and SB) are considered the major causes for obesity, phy of the adipocytes can, in fact, occur in different locations within
the fact that individuals exposed to a similar environment and lifestyle the body, including insulin-dependent tissues, like skeletal muscle,
may not necessarily gain the same degree of body weight and develop liver, and the adipose tissue itself.34 In addition to accumulation of ex-
obesity, suggests a strong influence of genetic factors.13 This is sup- cess fat within the adipose tissue, skeletal muscle and liver, ectopic fat
ported by early twin and adoption studies that observed strong herita- can accumulate around and within most organs, such as the heart,
bility of body mass index (BMI; kg/m2).14 liver, pancreas and kidney (Fig. 1),34 resulting in a number of abnormal-
Excess adiposity is typically accumulated over a long period of time, ities which can ultimately result in cardiometabolic chronic diseases.
resulting from a chronic positive energy balance, with daily caloric in- The excess adiposity characteristic of obesity may be responsible for
take exceeding energy expenditure. Although the positive chronic en- the insulin resistance of the skeletal muscle and the liver, but also within
ergy balance has been often thought to be exclusively the results of the adipose tissue itself.34–37
hypercaloric diet characteristic of the Western countries,15–17 the over- Although the exact mechanisms linking obesity to insulin resistance
all caloric intake has not changed as dramatically over the years as one are still being explored, preclinical data suggest that obesity alters the
may think,18 suggesting that other factors responsible for the overall re- intracellular insulin signaling in insulin-sensitive tissues and
duction of energy expenditure may be responsible, and in fact may be downregulates the expression of the insulin-responsive glucose trans-
the major contributors, for the current obesity epidemic. In support to porters exposed on the cell membrane that allows the flux of glucose in-
this concept, occupation-related PA19 as well as household manage- side the cells.38,39 Furthermore, because insulin has antilipolytic effects,
ment energy expenditure20 have declined significantly over the past the deterioration of its signaling caused by insulin resistance is associ-
50 years, providing evidence that reduced PA may play a major role in ated with a reduced suppression of lipolysis, resulting in a greater and
determining a chronic positive energy balance. constant release of free fatty acids (FFA) in the circulation. The release
Based on these assumptions, increased PA and reduced caloric intake of FFA by the adipose tissue contributes to a vicious cycle, often referred
should result in a chronic negative energy balance, finally resulting in as lipotoxicity, in which FFA can, in turn, increase hepatic and skeletal
weight loss. However, maintenance of body weight resulting from dis- muscle insulin resistance, and at later stages, impair insulin secretion
ruption of energy balance, for instance during caloric restriction- in predisposed individuals.40,41 Particularly, hepatic insulin resistance
induced weight loss, remains challenging due to several innate, com- results in an increased activation of the gluconeogenesis, promoting
pensatory mechanisms that return body weight to a ‘set-point’.21–24 fasting and postprandial hyperglycemia.41
This complex regulation of energy homeostasis involving a large num- In normal conditions and in a fed state, the increased level of circu-
ber of peripheral and central pathways may explain the lack of curative lating insulin binds to the dedicated receptor located on the membrane
measures of obesity, which typically target one or only few of them.21–24 of the adipocytes, which in turn stimulates the translocation of glucose-
For these reasons, as recently largely described in a state-of-the-art transporter type 4 (GLUT4) from the cytosol to the cell membrane,
review,3 we believe that preventing obesity may represent a much allowing the glucose to enter the cell.42 In mice, the deletion of adipose
more powerful and long-lasting tool to ultimately prevent the numer- tissue-specific GLUT4 induces insulin resistance in the skeletal muscle
ous cardiometabolic abnormalities associated with it. and the liver.38 These data suggest that therapeutics improving insulin
In the presence of a chronic positive energy balance, the adipocytes, receptor signaling resulting in augmented translocation of GLUT4,
the primary cells of adipose tissue, can grow in numbers such as drugs targeting the AMP-activated protein kinase, may improve
(i.e., hyperplasia) and in size (i.e., hypertrophy).22,25 In the initial insulin sensitivity and perhaps reduce the associated risk for T2DM. In
phase of weight gain, the size of the adipocytes increases, however, fact, obesity, particularly increased abdominal adiposity, is associated
when the size of the hypertrophic adipocytes reaches the limit of expan- with a markedly increased risk of T2DM.5,6,43,44 In the Health Profes-
sion for nutrients storage, preadipocytes can differentiate into more ma- sionals Follow-Up Study, 27,270 men were followed for 13 years in a
ture adipocytes.25 Such events ultimately result in the typical obesity prospective cohort study, to investigate the effects of BMI, but also of
phenotype characterized by both hypertrophy and hyperplasia of waist circumference (WC), a surrogate for visceral fat, on the risk for
 S. Carbone et al. / Progress in Cardiovascular Diseases 62 (2019) 327–333 329

Fig. 1. Accumulation of visceral and ectopic adipose tissue in the body and cardiometabolic abnormalities. Apo, apolipoprotein; FFA: free fatty acids; AT, adipose tissue; VLDL, very-low-
density lipoprotein. Modified with permission from Bastien et al.34

T2DM.45 A BMI between 27.2 and 54.2 kg/m2, representing the highest tissue is an endocrine organ able to produce several adipokines and cy-
quintile in the study, was associated with an 8-fold increased risk to de- tokines, the latter being recently targeted in an attempt to prevent
velop T2DM compared to those with a BMI b 22.8 kg/m2. Those in the T2DM.47 In the setting of adipose tissue expansion, activated adipose
highest quintile for WC (101.6–157.5 cm), however, presented an tissue macrophages can be recruited by chemokines and release proin-
even greater risk for T2DM, by about a 12- fold increased risk.45 These flammatory cytokines, which can increase lipolysis, which further con-
results suggest that the location of adipose tissue within the body may tributes to the increased release of FFA in the circulation
play a more important role than overall adiposity. Nevertheless, an in- (i.e., lipotoxicity), further worsening insulin signaling activity in adipose
creased BMI remains a risk factor for T2DM in absence of more accurate tissue, liver and skeletal muscle.41
measures of body fat distribution. Similarly, data from another prospec- Despite the clear increased risk of T2DM at greater levels of BMI,
tive cohort study, The Nurses' Health Study, in 74,419 women, found whether increased BMI causes T2DM requires additional investigations.
that increased BMI was also associated with a greater risk for T2DM, In the Diabetes Prevention Program (DPP), individuals with a mean BMI
however, the study also highlighted the different risk based on race of 34.0 kg/m2 receiving intensive lifestyle intervention aimed at achiev-
and ethnicities, with a greater risk for T2DM at a given BMI in Asians, ing at least 7% weight loss through dietary modifications, in addition to
Hispanics and blacks compared to whites.43 In fact, for each 5-unit in- 150 min per week of PA, presented a significant 58% reduction of the in-
crement of BMI, the relative risks for T2DM compared to whites were cidence of T2DM compared to those in the control group receiving stan-
1.43 for Asians, 1.76 for Hispanics, and 2.18 for blacks, respectively.43 dard lifestyle recommendations48; these marked benefits occurred
Another hypothesis which may drive obesity to insulin resistance despite the fact that average weight loss and PA were much less that an-
and ultimately T2DM is the inflammatory hypothesis.46 The adipose ticipated. The strongest predictor for T2DM prevention was, however,
330 S. Carbone et al. / Progress in Cardiovascular Diseases 62 (2019) 327–333

weight loss. For each kg of weight loss, individuals experienced a greater combination of those. As described above, the degree of weight loss
than16% relative risk reduction in the development of T2DM, even after seems to be an independent predictor for the remission of T2DM, even
adjustments for diet and PA.49 These results suggested that excess body after adjustments for diet and PA,49 however, in the DPP, in those not
weight, likely as result of excess adiposity, may not be just a marker, but, achieving the weight loss goal of 7% at 1 year, meeting the recom-
in fact, a cause of T2DM. mended level of PA of 150 min per week was still associated with a
Increased markers of chronic low-grade systemic inflammation in 44% reduction of T2DM, even after adjustments for changes in body
obesity are associated with incidence of T2DM46,50–52 and preclinical weight.49 Furthermore, an increase in PA of 5 metabolic equivalent of
data suggest that the resolution of such inflammation could prevent tasks (METs) after 3 years was also associated with a small, although
the development of T2DM in obesity and prediabetes. This hypothesis statistically significant, reduction in body weight of 0.43 kg.49 In addi-
was substantiated by preclinical animal data, in which the deletion of tion to the potential contribution to weight loss, increased levels of PA
the macromolecular complex NLRP3 inflammasome, responsible for are typically associated with an improved CRF,10,68–70 which is one of
the production of the pro-inflammatory cytokines interleukin [IL]-1β the strongest predictors for reduced CVD and all-cause mortality in
and IL-18, resulted in improved insulin sensitivity.53 The hypothesis the general population as well as those with chronic diseases, including
that the NLRP3 inflammasome may drive the insulin resistance state in- T2DM.10,71–76
duced by obesity was partially recently tested in over 4000 patients In a prospective study of 7804 men without T2DM followed for a pe-
with prediabetes and increased C-reactive protein (i.e., ≥2 mg/L) using riod of over 20 years,77 greater CRF defined as the highest quartile of
a targeted anti-inflammatory strategy (i.e., canakinumab: IL-1β mono- peak oxygen consumption (VO2) (49.8 mL•kg−1•min−1), the gold stan-
clonal antibody).47 Canakinumab failed to prevent T2DM,47 despite re- dard assessment of CRF,78,79 presented a 42% reduced risk for incidence
ducing major CVD events.54 We cannot exclude, however, that of T2DM compared to those in the lowest quartile. Of note, although the
additional proinflammatory cytokines are involved in the development highest quartile presented the greatest associated reduction with inci-
of T2DM in individuals at risk. NLRP3 inflammasome also produces an- dent T2DM, also quartile 2 (36.4 mL•kg−1•min−1) and quartile 3
other major proinflammatory cytokine, namely IL-18, which has been (41.5 mL•kg−1•min−1) were associated with a greater likelihood to pre-
involved in obesity-induced inflammation and insulin resistance.55–59 vent T2DM, suggesting that any improvements in CRF would be
In a preclinical study of high-saturated fat and high-sugar diet desirable.77 Similarly, in a 17-year follow-up study in women without
(i.e., Western diet)-induced metabolic abnormalities and cardiac T2DM at baseline, CRF lower than 7 MET (1 MET = 3.5 mL•kg−1•min−1)
dysfunction,60 an oral inhibitor of the NLRP3 inflammasome was associ- measured with a treadmill exercise test was associated with a 3-fold in-
ated with improved cardiac function; but glucose metabolism abnor- creased risk for T2DM compared to those with CRF ≥ 10 MET.80 Of note,
malities were not improved.61 Taken together, these data do not these associations were only true in the overweight and obesity groups,
support the role of the inhibition of the NLRP3 inflammasome in im- while in those women with a body weight within normal range, the
proving glucose metabolism and preventing the onset of T2DM in indi- unfit women did not present a significantly greater risk for T2DM com-
viduals with obesity, however, it suggests that such a strategy may still pared to the fit ones.80 A recent meta-analysis of 13 studies, including
prevent or even treat the CV abnormalities induced by obesity and per- 1,601,490 patients, has shown that after controlling for adiposity, each
haps T2DM. increase in CRF by 1 MET was associated with a linear 8% reduction in
To this regard, despite significant improvements made in the treat- future T2DM (Fig. 2).81
ment of T2DM in the last decades, patients with T2DM still present an
unacceptably high risk for CVD, which remains the leading cause of PA and ET to increase CRF in T2DM
death in this population. This highlights the need for greater efforts of
clinicians and researchers to develop effective strategies to reduce the In addition to the strong association between improved CRF and re-
burden of CVD in T2DM. We believe that such therapies should be de- duced risk for T2DM, the role of CRF has been also investigated in those
veloped and implemented even in absence of improvements in typical with established disease. In a recent analysis of 150 patients with T2DM,
T2DM-related endpoints, such as improved glycemic control, which, CRF (i.e., peak VO2) was found to be markedly reduced, even after ad-
to date, have not consistently been shown to reduce major CVD events, justments for fat-free mass,8 which has been proposed to be a better as-
but rather microvascular complications.62,63 sessment of CRF,82 particularly in individuals with overweight and
obesity, in which the use of CRF adjusted by total body weight may re-
PA and ET to improve body weight and CRF to prevent T2DM sult in an underestimated CRF.83–85 These data confirmed what was pre-
viously described in a larger analysis of 5145 individuals with T2DM.86
As discussed at length elsewhere, intentional weight loss induced by
caloric restriction, but also pharmacologic and surgical interventions, in
the setting of a comprehensive lifestyle modification program, remains
the cornerstone therapy to improve insulin sensitivity and in some cir-
cumstances to prevent the incidence of T2DM in individuals with obe-
sity and prediabetes.64 The amount of weight loss required to result in
clinically significant improvements can vary, but even small improve-
ments in body weight of the magnitude of 2.6 kg to 5 kg have been as-
sociated with reduced incident T2DM.48 Those with lower FM before the
interventions seem to present greater benefits in terms of weight loss.48
Of note, in addition to caloric restriction, improvements in quality of
diet, such as an increase in dietary unsaturated fatty acids consumption,
may also prevent T2DM, even in absence of weight loss.65–67
Most clinical trials investigating the effects of weight loss in
preventing T2DM in individuals with overweight/obesity and prediabe-
tes typically involve a multidisciplinary comprehensive approach, in-
cluding dietary changes, such as improvements in quality of diet, with
or without caloric restriction, but also strategies to increase daily PA Fig. 2. Linear association between improvement in cardiorespiratory fitness and reduced
and/or ET, making it difficult to differentiate whether the benefits on risk for type 2 diabetes mellitus. RR, relative risk. Modified with permission from Tarp
metabolic outcomes are the result of dietary modifications, PA/ET or a et al.81
 S. Carbone et al. / Progress in Cardiovascular Diseases 62 (2019) 327–333 331

Furthermore, improvements in CRF are also typically associated with significantly lower sedentary time by 0.8-h/day compared to the control
improved cardiometabolic risk factors in patients with T2DM. In a group.93 Importantly, the improvements in PA and SB also resulted in
sub-analysis of 3942 patients of The Action for Health in Diabetes impressive improvements in CRF (+ 2.6 mL•kg−1•min−1), also associ-
Study (Look AHEAD),87 one of the largest multicenter clinical trials ated with a greater lower body strength, whereas upper body strength
ever performed investigating the effects of intensive lifestyle interven- was unchanged.93 Interestingly, no improvements in HbA1c nor lipids
tions on CVD events in T2DM,88 improvements in CRF (i.e., MET) were were reported, while there were significant reductions in fasting glyce-
associated with a greater reduction in glycated hemoglobin (HbA1c). mia (−9.15 mg/dL) and systolic blood pressure (−2.88 mmHg).93
Another analysis of this study of 4408 patients showed that increased With regards to ET, in a meta-analysis including 266 individuals with
CRF was associated with improved cardiometabolic risk factor, such as T2DM, a mean ET of 49-min session, 3.4 times per week for 20 weeks,
glucose, high-density lipoprotein cholesterol, triglycerides and diastolic was associated with an almost 12% increase in peak VO2, with greater
blood pressure, even after adjustments for the degree of weight loss.89 benefits found at greater intensity of ET.94 Even shorter duration of ET
In a study of 4156 veterans with T2DM, each increase in 1 MET was as- can, however, result in improvements in CRF. In a small pilot study of
sociated with a 12% lower risk for all-cause mortality.90 Importantly, 16 individuals with T2DM, an 8-week combined ET program of aerobic
those individuals with a CRF N 5 MET had a marked reduction in all- ET and resistance ET was associated with a significant improvement of
cause mortality, ranging from 35% to 55%, compared with those with 1.7 mL•kg−1•min−1 in peak VO2, in addition to improvements in muscle
lower CRF90 strength, FM, HbA1c and fasting glycemia.95 In a larger randomized con-
As mentioned above, PA and ET remain the strongest tools to im- trolled trial of 262 sedentary individuals with T2DM, the role of aerobic
prove CRF,10,73,74 which may in turn result in improved clinical out- ET and resistance ET alone or combined was investigated in a 9-month
comes. Approaches aimed at increasing PA and at reducing SB are program.96 Importantly, aerobic ET and resistance ET alone did not re-
effective strategies to improve CRF in the general population, however, sult in a significant improvement in CRF compared to the control
their effects in individuals with T2DM with "have not been explored ex- group, however, the combined ET program resulted in a significant
tensively until very recently. Nevertheless the American Diabetes Asso- 1.0 mL•kg−1•min−1 increase in peak VO2.96 The individual ET groups
ciation (ADA) recommends that most adults with T2DM should engage only improved exercise time and estimated METs, which were, how-
in 150 min or more of moderate-to-vigorous PA per week or 75 min of ever, still lower that what was found in the combined ET group.96
vigorous PA in younger individuals, with no N2 consecutive days with- The beneficial effects of PA and ET are numerous and have been re-
out PA.91 Such recommendations are similar to what is recommended cently reviewed elsewhere.10 Briefly, improvements in mitochondrial
in the general population.92 functionality, skeletal muscle, cardiac muscle and endothelial function
In the randomized Italian Diabetes and Exercise Study 2 (IDES_2), have been reported in both clinical and preclinical data (Fig. 3).
300 physically inactive patients with T2DM were assigned and followed
for a median follow-up of 3 years to a behavioral intervention to in- Conclusions
crease PA and reduce SB (1 individual theoretical counseling session
and 8 individual biweekly theoretical and practical counseling sessions Chronic positive caloric balance from unhealthy dietary habits, re-
per year), or to a control group receiving standard therapy following duced PA and increased SB result in increased adiposity, eventually
the ADA guidelines.93 The study resulted in a significant improvement leading to adipose tissue remodeling and obesity. This excess adiposity,
in objectively measured PA with an accelerometer by 3.3 MET-hour/ in turn, markedly increases the risk for cardiometabolic disease, partic-
day compared to the control group, reflected in a significant increase ularly T2DM. Importantly, in patients with obesity, T2DM can be
in both light-intensity PA and moderate-to-vigorous intensity PA.93 prevented by implementing lifestyle behavior modifications, including
The patients assigned to the behavioral intervention also presented a improvements in diet, increased PA, ET and perhaps SB, ultimately

Fig. 3. Detrimental effects of sedentary behavior and physical inactivity and the beneficial effects of physical activity and exercise training in mitochondria, skeletal muscle, myocardium,
and conduit arteries. AGE, advanced glycation end products; Akt, protein kinase B; β-HAD, beta-hydroxyacyl CoA dehydrogenase; CRP, C-reactive protein; FOXO3a, forkhead box O3; DNA,
deoxyribonucleic acid; IL-6, interleukin-6; MHC, myosin heavy chain; mRNA, messenger ribonucleic acid; MuRF-1, muscle RING-finger protein-1; MMP, matrix metalloproteinase; mTOR,
mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; PGC-1α, peroxisome proliferator-activated receptor
gamma coactivator 1-alpha; PI3K, phosphoinositide 3-kinase; SERCA2a, sarcoplasmic reticulum calcium adenosine triphosphatase; SIRT3; nicotinamide adenine dinucleotide dependent
deacetylase sirtuin-3 SOD. Modified with permission from Lavie et al.10
332 S. Carbone et al. / Progress in Cardiovascular Diseases 62 (2019) 327–333

leading to improved CRF. Clearly, greater CRF is, in fact, associated with 25. Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol
2015;208:501-512.
reduced risk for CVD events and mortality and all-cause mortality. Cer- 26. Harms M, Seale P. Brown and beige fat: development, function and therapeutic po-
tainly, the prevention of obesity in the first place would be desirable, tential. Nat Med 2013;19:1252-1263.
however, in those with established disease, we believe that clinicians 27. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown ad-
ipose tissue in adult humans. N Engl J Med 2009;360:1509-1517.
should put forth a greater effort to implement lifestyle modifications 28. Celi FS. Brown adipose tissue–when it pays to be inefficient. N Engl J Med 2009;360:
to improve patients' quality of life and to reduce the unacceptably 1553-1556.
high healthcare costs associated with obesity, T2DM and their related 29. Cypess AM, Weiner LS, Roberts-Toler C, et al. Activation of human brown adipose tis-
sue by a beta3-adrenergic receptor agonist. Cell Metab 2015;21:33-38.
complications, especially from CVD. 30. Mirbolooki MR, Upadhyay SK, Constantinescu CC, Pan ML, Mukherjee J. Adrenergic
pathway activation enhances brown adipose tissue metabolism: a [(1)(8)F]FDG
Funding support PET/CT study in mice. Nucl Med Biol 2014;41:10-16.
31. Mirbolooki MR, Constantinescu CC, Pan ML, Mukherjee J. Targeting presynaptic nor-
epinephrine transporter in brown adipose tissue: a novel imaging approach and po-
Salvatore Carbone is supported by a Career Development Award tential treatment for diabetes and obesity. Synapse 2013;67:79-93.
19CDA34660318 from the American Heart Association. 32. Ruiz JR, Martinez-Tellez B, Sanchez-Delgado G, Osuna-Prieto FJ, Rensen PCN, Boon
MR. Role of human brown fat in obesity, metabolism and cardiovascular disease:
strategies to turn up the heat. Prog Cardiovasc Dis 2018;61:232-245.
Declaration of competing interest 33. Chobot A, Gorowska-Kowolik K, Sokolowska M, Jarosz-Chobot P. Obesity and
diabetes-not only a simple link between two epidemics. Diabetes Metab Res Rev
2018;34, e3042.
None.
34. Bastien M, Poirier P, Lemieux I, Despres JP. Overview of epidemiology and contribu-
tion of obesity to cardiovascular disease. Prog Cardiovasc Dis 2014;56:369-381.
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