Leptin

Background: Cachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated. Methods: 140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months. Results: Ghrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 -1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 -0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease. Conclusion: Ghrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

This prospective, randomized study investigated the effect of exercise on leptin, insulin, cortisol and lipid profiles in obese children. A total of 40 obese boys aged 10-12 years with a body mass index (BMI) ≥ 30 kg/m 2 were randomly separated into an exercise group (n = 20) that underwent a 12-week aerobic exercise programme and a non-exercise (control) group (n = 20). The BMI, low-density lipoprotein, cortisol, leptin and insulin levels were significantly lower in the exercise group after 12 weeks compared with baseline values, whereas highdensity lipoprotein levels were significantly higher. In contrast, in the control group, low-density lipoprotein, cortisol and leptin levels were significantly higher after 12 weeks compared with baseline values while high-density lipoprotein levels were significantly lower. These findings indicate the importance of regular exercise in the regulation of body weight and protection against cardiovascular risk factors in obese children.

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (&gt;10%) and BMI (&gt;-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively wi...

Obesity is one of risk factors of various chronic diseases and malignancy. It may result from excess accumulation of body fat. This condition may be caused by dysfunction of appetite-regulating pathways and energy balance due to leptin resistance. Leptin, a 16 kDa hormone, is the most important regulator of appetite and energy balance in the body. Most individuals with obesity have leptin resistance characterized by increased leptin blood level.

Breast cancer is the most common malignancy among women worldwide. There is extensive literature on the relationship between body weight and breast cancer risk but some doubts still remain about the role of adipokines per se, the role of insulin and glucose regardless of obesity, as well as the crosstalk between these players. Thus, in this study, we intend to determine the relation between body mass index (BMI), glycaemia, insulinemia, insulin-resistance, blood adipokine levels and tumour characteristics in a Portuguese group of pre- and postmenopausal overweight/obese women with breast cancer. We evaluated clinical and biochemical data in 154 participants, divided in 4 groups: (1) control with BMI &lt;25 kg/m(2), n = 29 (CT); (2) control with BMI &gt;25 kg/m(2), n = 48 (CTOb); (3) breast cancer with BMI &lt;25 kg/m(2), n = 30 (BC); and (4) breast cancer with BMI &gt;25 kg/m(2), n = 47 (BCOb). In women with breast cancer, we also performed tumour characterization. We found that BCO...

Background: To explore the changes in plasma leptin levels of rats with induced Toxoplasma gondii infection. Methods: The study was conducted on 20 Spraque-Dawley type adult male rats, which were equally divided into two groups. Group 1, general control group. Group 2, infection group (rats in this group were infected with live Toxoplasma gondii parasite, which was injected in 0.5 ml serum physiologic through intraperitoneal route, so that 10-12 parasites were seen in the area under a light microscope). Blood samples collected from all animals 4 weeks after the infection were analyzed to determine plasma leptin levels (RIA). Results: There was no signifi cant difference between the body weights of groups 1 and 2 at the end of the study. Plasma leptin levels in the infection group (group 2) were signifi cantly higher than those in group 1 (p<0.01). Conclusion: Toxoplasma gondii infection can cause an increase in leptin secretion without changing body weight in a period of 4 weeks in rats (Tab. 1, Ref. 25).

Recent evidence highlights the important role of the brain in the control of glucose homeostasis. Hypothalamic centers sense the availability of peripheral nutrients via redundant and overlapping nutrient-induced peripheral signals such as leptin and insulin and via direct metabolic signaling. Responding to nutrient availability, these hypothalamic regions in turn exert a negative feedback not only on food intake but also on endogenous glucose production. Disruptions in the mechanisms of central nervous system nutrient sensing alter these homeostatic responses and contribute to the pathophysiology of obesity and type 2 diabetes. In this review, we discuss the neural and molecular pathways so far identified as possible targets for therapeutic intervention.

A prerequisite for successful embryo implantation is adequate preparation of receptive endometrium and the establishment and maintenance of a viable embryo. The success of implantation further relies upon a two-way dialogue between the embryo and uterus. However, molecular bases of these preimplantation and implantation processes in humans are not well known. We performed genome expression analyses of human embryos (n ϭ 128) and human endometria (n ϭ 8). We integrated these data with protein-protein interactions in order to identify molecular networks within the endometrium and the embryo, and potential embryo-endometrium interactions at the time of implantation. For that, we applied a novel network profiling algorithm HyperModules, which combines topological module identification and functional enrichment analysis. We found a major wave of transcriptional down-regulation in preimplantation embryos. In receptive-stage endometrium, several genes and signaling pathways were identified, including JAK-STAT signaling and inflammatory pathways. The main curated embryo-endometrium interaction network highlighted the importance of cell adhesion molecules in the implantation process. We also identified cytokine-cytokine receptor interactions involved in implantation, where osteopontin (SPP1), leukemia inhibitory factor (LIF) and leptin (LEP) pathways were intertwining. Further, we identified a number of novel players in human embryo-endometrium interactions, such as apolipoprotein D (APOD), endothelin 1 (END1), fibroblast growth factor 7 (FGF7), gastrin (GAST), kringle containing trnasmembrane protein 1 (KREMEN1), neuropilin 1 (NRP1), serpin peptidase inhibitor clade A member 3 (SERPINA3), versican (VCAN), and others. Our findings provide a fundamental resource for better understanding of the genetic network that leads to successful embryo implantation. We demonstrate the first systems biology approach into the complex molecular network of the implantation process in humans. (Molecular Endocrinology 26: 203-217, 2012) S uccessful embryo implantation is an absolute requirement for the reproduction of mammalian species. In humans, implantation involves complex interactions between the embryo and the maternal endometrium, all of which must be performed within an optimal time frame.

In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.

Leptin decreases food intake, body weight and fat mass while sparing lean mass. Although mouse leptin (ML) and rat leptin (RL) are 95.9% identical, our impression from previous studies was that they were not equally potent in rats. Thus, in the present study, 0 g (vehicle) or 10 g of ML or RL was injected into the lateral ventricle of rats (eight per treatment) once a day for four consecutive days. Body temperature, body weight, food intake and water intake were measured daily. Intrascapular and perirenal brown fat pads, white fat tissues (retroperitoneal, epididymal and inguinal fat pads) and the gastrocnemius muscle were collected and weighed 24 h after the last treatments. Body temperature was not affected by either ML or RL. Both ML and RL caused significant reductions in food intake (P < 0.05), and there was no difference between them. ML and RL also similarly inhibited water intake on days 2 and 3 (P < 0.05). By day 5 both ML-and RL-treated rats had lost weight (11.6 and 15.4 g, respectively), while vehicle-treated rats gained weight (6.8 g). Weights of retroperitoneal and epididymal fat pads, but not other tissues, were reduced similarly by both leptin treatments (P < 0.05). However, an increased apoptotic response was detected in the retroperitoneal fat tissue of RL-but not ML-treated rats (P < 0.05). These results suggest that RL is more effective than ML in inducing apoptosis in retroperitoneal fat tissue after i.c.v. injection in rats.

Apoptotic myocyte cell death, diastolic dysfunction and progressive deterioration in LV pump function, characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG)-transmits danger signals in cardiac muscle cells (CMC). The growth factor adapter protein, p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here, we demonstrate interventions that attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser-36), inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes (ARVM) obtained by enzymatic dissociation were transduced with mutant36 p66ShcA (mu-36) dominant negative expression vector and plated in serum free media (SFM) containing 5 mM or 25 mM glucose. At HG, ARVM exhibit marked increase in reactive oxygen species (ROS) production, upregulation of phospho-Ser-36, collapse of mitochondrial transmembrane potential (Δψm) and increased formation of p66ShcA/cytochrome c complexes. These indices of oxidative stress were accompanied by 40% increase in apoptosis and upregulation of cleaved caspase 3 and the apoptosis related proteins p53 and Bax. To test if p66ShcA functions as a redox sensitive molecular switch in vivo, we examined hearts of male Akita diabtic nonobese (C57BL/6J) mice. Immunoblot analysis detected upregulation of phospho-Ser-36, translocation of p66ShcA to mitochondria and formation of p66ShcA/cytochrome c complexes. Conversely, correction of HG by adenoassociated viral delivery of leptin

The effects of continuous or intermittent access to a high-caloric (HC) diet, always offered in addition to standard chow, on body mass and leptin resistance were analyzed in female C57BL/6J mice. Susceptibility for diet-induced obesity (DIO) was apparent from the marked preference for the HC diet. Continuous HC diet feeding of mice at 4 weeks of age induced leptin resistance within 2 weeks and massive gains in body mass, although with increasing inter-individual variability in the inbred strain considered to be isogenic. In adult mice receiving HC diet for the first time, leptin treatment failed to reduce energy intake first after 11 days of HC diet feeding, but became effective again within 3 days after HC diet withdrawal. In mice with a history of several preceding periods of access to the HC diet totalling N 30 days, supplementary HC diet abolished the anorectic effect of leptin treatment within only 3 days and it reappeared not earlier than 11 days after HC diet withdrawal. Thus, in the investigated DIO-prone mouse strain both, the loss of responsiveness to leptin under HC diet and its recovery after HC diet withdrawal strongly depended on the dietary history. Recovery from leptin resistance during periods of intermittent chow feeding was associated with losses of body mass that did not completely compensate for the obesity-inducing effect of the preceding HC diet.

It is generally agreed that physiological levels of melatonin, a hormone secreted by the pineal gland, are important in protecting against oxidative stress-induced tissue damage. We investigated the effects that pinealectomy and the administration of exogenous melatonin have on the brains, testes, duodena and stomachs of rats. Pinealectomized (Px) and sham-operated (non-Px) rats were used. We evaluated structural changes, and catalase (CAT), reduced glutathione (GSH), super oxide dismutase (SOD) and malondialdehyde (MDA) levels. The rats were divided into the following five groups (eight rats in each group): sham (non-Px), Px+ vehicle, Px+ melatonin (10 mg/kg given daily intraperitoneally for a week), melatonin and ethyl alcohol. The antioxidant levels in the tissue of Px rats were significantly lower than in those of the sham group. Administering melatonin significantly increased antioxidant levels (p &lt; 0.05). The Px rats also showed a significant increase in MDA levels when com...

OBJECTIVE The role of leptin in the acute stress response to extracorporeal circulation has been well documented, however, the relationship between leptin and zinc has not been investigated previously. We aimed to research the circulating leptin, zinc, and copper levels before, during, and after the extracorporeal circulation, and effect of preoperative zinc administration to these. METHODS Twenty patients who were taken to elective coronary artery bypass grafting operations using extracorporeal circulation were taken to this research and divided into two equal groups (n1, n2). In both groups blood samples were taken just before the operation (T0), at the end of operation (T1), and at the first postoperative day (T2). In the second group (n2) oral zinc (50 mg, once a day) was administered to patients for 5 days, preoperatively. The serum leptin, zinc, and copper levels were studied. RESULTS In group n1 circulating leptin levels were significantly increased at T2 when compared to T0 ...

Background: Brain-derived neurotrophic factor (BDNF) plays important roles in the central regulation of food intake and body weight control. However, little is known about the role of BDNF in childhood obesity. Objective: To investigate the relationship between plasma levels of BDNF and anthropometric factors, metabolic derangements due to obesity, adipocytokine levels and birth weight in obese Japanese children. Subjects and methods: Sixty-six obese Japanese children aged from 5 to 15 years old were enrolled. The age-matched control group consisted of 32 non-obese healthy children. The plasma levels of BDNF and adipocytokines (leptin and adiponectin) were assayed using ELISA techniques. Results: The mean BMI Z-scores were −0.67, +2.15 and +3.39 for the non-obese control children, obese (BMI ≥ 90th percentile, <99th percentile) and morbidly obese (BMI ≥ 99th percentile), respectively. The plasma levels of BDNF were significantly decreased in the morbidly obese children compared with the levels in the obese and non-obese control children (507 ± 33 pg/ml vs. 626 ± 46 pg/ml, 621 ± 35 pg/ml, p < 0.05). Univariate linear regression analysis showed that the plasma level of BDNF was positively correlated with birth weight (r = 0.264, p < 0.05) and inversely * e64 S. Araki et al. correlated with the BMI Z-score (r = −0.314, p < 0.05). Multivariate forward stepwise linear regression analysis revealed that the birth weight and BMI Z-score are independent predictors of the plasma BDNF level. Conclusion: The plasma level of BDNF, which is decreased in morbidly obese children, is associated with birth weight and the BMI Z-score. Our results suggest that BDNF may play important roles in the development and pathophysiology of childhood obesity.

Cocaine-and amphetamine-regulated transcript (CART) is expressed in the hypothalamus, and putative peptides encoded by CART potently inhibit feeding when administered centrally. CART is strongly down-regulated in the lateral hypothalamic area and the arcuate nucleus in animal models of obesity with disrupted leptin signaling. Here we have used in situ hybridization and immunohistochemistry to study CART expression in mice homozygous for the anorexia (anx) mutation which are characterized by a much reduced food intake and premature death. anx /anx mice had significantly decreased levels of CART mRNA label and peptide-immunoreactive cell bodies and fibers in the arcuate nucleus and a lower number of detectable CART-expressing cells in the dorsomedial hypothalamic nucleus / lateral hypothalamic area. Moreover, serum leptin levels were significantly lower in anx /anx mice compared to normal littermates, most likely due to the prominent depletion of body fat in these animals. The decrease in the anorexigenic agents leptin and CART, may reflect a compensatory down-regulation in response to the energy-deprived state of anx /anx mice. Alternatively, the reduced arcuate CART expression may be a consequence of a molecular defect in the arcuate nucleus of these animals.

The bone marrow contains mesenchymal stem cells (MSCs) that differentiate to the osteogenic and adipogenic lineages. The fact that the decrease in bone volume of age-related osteoporosis is accompanied by an increase in marrow adipose tissue implies the importance that the adipogenic process may have in bone loss. We previously observed that MSCs from control and osteoporotic women showed differences in their capacity to differentiate into the osteogenic and adipogenic pathways. In vitro studies indicate that bone marrow stromal cells are responsive to leptin, which increases their proliferation, differentiation to osteoblasts, and the number of mineralized nodules, but inhibits their differentiation to adipocytes. The aim of the present report was to study the direct effect of leptin on control and osteoporotic MSCs analyzing whether the protective effect of leptin against osteoporosis could be expressed by inhibition of adipocyte differentiation. MSCs from control, and osteoporotic donors were subjected to adipogenic conditions, in the absence or in the presence of 62.5 nM leptin. The number of adipocytes, the content of PPARg protein, and mRNA, and leptin mRNA were measured by flow cytometry, Western blot, and RT-PCR, respectively. Results indicate that control and osteoporotic MSCs differ in their adipogenic potential as shown by expression of active PPARg protein. Leptin exerted an antiadipogenic effect only on control MSCs increasing the proportion of inactive phosphorylated PPARg protein. Finally, results obtained during adipogenesis of osteoporotic cells suggest that this process is abnormal not only because of increased adipocyte number, but because of impaired leptin cells response.

OBJECTIVE In the present study we aimed at investigating leptin levels in professional male athletes who have been exercising regularly for a long time and leptin levels in healthy sedentary males. METHODS The study included 10 male professional football players and 17 healthy sedentary males. The relations between groups in terms of leptin levels, Max VO2 levels, blood lactic acid levels before and after exercise and effort durations were investigated. RESULTS It was found in the study that although BMI of professional male athletes was higher than that of the healthy sedentary males, leptin levels of the former were significantly lower (p&lt;0.01), while VO2Max levels (p&lt;0.05) and test periods (p&lt;0.01) were significantly higher than those in the latter. As for lactic acid levels after exercise and between groups, these were also higher in athletes, but the difference was not statistically significant (p&gt;0.05). CONCLUSION Leptin levels of those who exercised regularly were...

Anorexia nervosa (AN) is characterized by self-induced starvation leading to severe weight and fat loss. In the present study, we measured fasting plasma levels of adiponectin, leptin, resistin, insulin and glucose in 10 women with a restrictive type of AN and in 12 healthy women (C). Insulin sensitivity was determined according to homeostasis model assessment of insulin resistance (HOMA-R). Plasma resistin, leptin and insulin levels were significantly decreased, whereas plasma adiponectin levels were significantly increased in patients with AN compared to the C. HOMA-R was significantly decreased in patients with AN compared to the C group. Plasma adiponectin and leptin concentrations negatively and positively correlated with the body mass index and percentage body fat in both groups. Plasma adiponectin levels were negatively related to plasma insulin levels in the AN group only. In conclusion, we demonstrated that AN is associated with significantly decreased plasma leptin and res...

Objective: To understand the association between ovarian hormones, non-acute satiety hormones and craving calorie dense foods in the luteal phase. Methods: 17 premenopausal women, mean age 23.2 y, mean BMI 22.4 kg/m 2 with regular menstrual cycles were studied during late follicular (FP) and luteal phases (LP). Estradiol, progesterone, DHEAS, SHBG, insulin and leptin, were measured in fasting samples. The validated Food Craving Inventory was used to record the types of foods volunteers habitually ate-rich in fat, carbohydrate or sweet taste, as well as craved during the LP of their menstrual cycle. Results: Estradiol was inversely associated with leptin in FP (r =-0.62, p = 0.01). Leptin was inversely associated with habitual intake of sweet foods, in both phases (FP: r =-0.64, p = 0.01; LP: r =-0.63, p = 0.01). SHBG in LP was positively associated with craving sweet and carbohydrate rich foods. Hierarchical cluster analysis revealed two groups of women, one with high estradiol, high estradiol/leptin ratio, high sweet and carbohydrate cravings (p<0.05); the other group had lower estradiol, lower estradiol/leptin ratio, and reported less craving. Conclusions: The estradiol-leptin axis may be a determinant of luteal phase craving and habitual food intake in menstruating women.

performed and body mass index (weight (kg)/height (m) 2 ) measured were studied. Overweight was defined as a body mass index greater than or equal to 25. On the basis of serologic results, the participants were categorized into three H. pylori status groups: H. pylori-positive and cytotoxin-associated gene A (cagA)-positive (H. pylori þ cagA þ ), H. pylori-positive and cagA-negative (H. pylori þ cagA ÿ ), and H. pylori-negative (H. pylori ÿ ). Of the 7,003 subjects with complete body mass index and H. pylori data, 2,634 (weighted percentage, 22.9%) were H. pylori þ cagA þ , 1,385 (15.1%) were H. pylori þ cagA ÿ , and 2,984 (62.0%) were H. pylori ÿ . The adjusted odds of being overweight were 1.17 (95% confidence interval: 0.98, 1.39; p ¼ 0.075) for the H. pylori þ cagA þ group and 0.99 (95% confidence interval: 0.80, 1.22; p ¼ 0.92) for the H. pylori þ cagA ÿ group in comparison with H. pylori ÿ subjects.

The aim of this study was to evaluate the changes in the ghrelin, leptin, and fat levels in the foremilk and hindmilk and the possible relationship between these levels with the age and growth of term healthy infants. Sixty-two babies were subdivided (according to their nutrition) into breastfed (BF), formula-fed (FF), and BF plus FF (BF + FF) groups. The total and active ghrelin and tryglyceride levels and the total cholesterol levels in the foremilk and hindmilk were studied at the first and second visits (mean of the second and fifth months, respectively). At both visits, the total and active ghrelin and the total cholesterol levels were lower in the hindmilk than in the foremilk. However, the triglyceride levels were higher in the hindmilk than in the foremilk (p < 0.001). The leptin levels were also higher in the hindmilk, but this difference was not statistically significant. At the second visit, the mean total foremilk ghrelin (p < 0.01), leptin (p < 0.05), tryglyceride (p < 0.001), and cholesterol (p < 0.01) levels in the BF group were decreased compared with the levels at the first visit, whereas the active ghrelin levels increased (p < 0.001). At the second visit, we observed a 3.5% increase in the body mass index in BF infants, a 14.6% increase in FF infants, and an 11.8% increase in BF + FF infants (p < 0.01). The foremilk leptin levels were lower in the BF + FF group than in the BF group at both visits. In conclusion, at the first and second visits, the decreased ghrelin and increased tryglyceride and leptin levels in the hindmilk might be associated with the important role of self-control when feeding BF infants. The stable content of formulas might be associated with a lack of self-control during feeding and increased nutrition. Changing the breast milk ghrelin, leptin, and fat levels between the foremilk and hindmilk and between the first and second visits might explain the differences in the weight gain patterns of BF and FF infants.

Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-andactivator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.

The association between morbid obesity and hyperhomocysteinemia (HH) remains controversial and the nature of this relationship needs to be clarified as several metabolic, lipidic, inflammatory and anthropometric alterations that accompany morbid obesity may be involved. In 66 morbidly obese patients, 47 women and 19 men aged 41 ± 12 years and 66 normo-weight subjects, 43 women and 23 men, aged 45 ± 11 years, we determined homocysteine (Hcy) levels along with lipidic, anthropometric, inflammatory and insulin resistance markers. In addition, we investigated the effect of Metabolic Syndrome (MS) and its components on Hcy levels. Obese patients had statistically higher Hcy levels than controls: 12.76 ± 5.30 M vs. 10.67 ± 2.50 M; p = 0.006. Moreover, morbidly obese subjects showed higher waist circumference, glucose, insulin, HOMA, leptin, triglycerides, fibrinogen, C reactive protein (CRP) (p < 0.001, respectively), and lower vitamin B12 (p = 0.002), folic acid and HDL-cholesterol (p < 0.001, respectively). In the multivariate regression analysis, waist circumference, glucose, leptin and folic acid levels were independent predictors for Hcy values (p < 0.050). When obese patients were classified as having MS or not, no differences in Hcy levels were found between the two groups (p = 0.752). Yet when we analysed separately each MS component, only abdominal obesity was associated with Hcy levels (p = 0.031). Moreover when considering glucose >110 mg/dL (NCEP-ATPIII criteria) instead of glucose intolerance >100 mg/dl (updated ATPIII criteria), it also was associated with HH (p = 0.042). These results were confirmed in the logistic regression analysis where abdominal obesity and glucose >115 mg/dL constitute independent predictors for HH (OR = 3.

As in Lymnaea stagnalis NPY plays a key role in regulating energy flows but has no effect on food intake, two important questions arise: 1) How is the amount of food consumed related to energy storage? 2) Can we give a molecular explanation for this alteration in function of NPY during evolution? Recent data have shown that also in Lymnaea a leptin-like factor is produced by glycogen storing cells which inhibits food intake, a Lymnaea storage feedback factor (LySFF). So, food consumption seems in balance with the amount of energy stored in this animal. We suppose that NPY neurons in Lymnaea have receptors for LySFF so that their activity in regulating energy homeostasis reflects the amount of stored energy. By comparing the molecular structure of NPYs in invertebrates it became clear that only molluscan and arthropod NPY are synthesized from a prohormone similar to vertebrate NPYs and should be considered as real invertebrate homologs of NPY. Based on pharmacological data we suppose that the identified Lymnaea NPY receptor is a Y1 subtype. This might explain that LyNPY has no effect on food intake in Lymnaea as this function of NPY in mammals is regulated through the Y5 subtype receptor.

Animal models of hepatic steatosis and steatohepatitis have improved our understanding of the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Three models, genetically obese ob/ob mice, lipoatrophic mice and normal rats fed choline-de®cient, methionine-restricted diets, have been particularly informative. All support the multiple`hit' hypothesis for NAFLD pathogenesis that suggests that fatty livers are unusually vulnerable to oxidants and develop steatohepatitis when secondary insults generate sucient oxidants to cause liver cell death and in¯ammation. Steatohepatitis, in turn, increases sensitivity to other insults that induce hepatic ®brosis, promoting the evolution of cirrhosis. Early during NAFLD pathogenesis, inhibitor kappa kinase beta (IKKb), an enzyme that induces tumour necrosis factor alpha (TNFa) and other proin¯ammatory cytokines, is activated and this causes insulin resistance. Inhibition of IKKb or TNFa improves insulin sensitivity, steatosis and steatohepatitis in animals, suggesting novel strategies to prevent and treat early NAFLD in humans.

Leptin, a protein hormone secreted by adipocytes, plays an important role in energy homeostasis and regulation of body composition. We previously observed that acute feed restriction resulted in a rapid decline in concentrations of leptin in obese pony mares. This acute response prompted us to characterize the temporal changes in concentrations of leptin, GH, and insulin in obese pony mares during the transition between fed and feed-restricted conditions. Nine obese pony mares of mixed breed, previously maintained on fescue pasture, were randomly allotted to 2 groups.

The objective of this study was to evaluate the effects of ovariectomy (i) and ad libitum feeding (ii) on energy intake, body weight (BW), body composition, thyroid status, leptin and ghrelin plasma concentrations. Four young adult female Beagle dogs were fed a maintenance diet for 6 weeks prior to ovariectomy, then 6 months after. Food allowance was adjusted in order to maintain optimal BW. Then, a diet slightly higher in energy concentration was fed ad libitum for 4 months. The maintenance diet was then fed ad libitum for one additional month. The maintenance of optimal BW after ovariectomy required a significant decrease in energy allowance. No increase in fat mass was observed. Ghrelin concentration remained unchanged. During the first month of ad libitum feeding, plasma ghrelin concentration and energy intake increased, then they decreased. Mean BW, plasma leptin, thyrotropin (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) concentrations significantly increased over the study. The BW increase was exclusively due to an increase in body fat. In conclusion, energy allowance should be strictly controlled in spayed female dogs. The results suggest that in dogs, thyroid hormones, leptin and ghrelin concentrations change in response to a positive energy balance in an attempt to limit weight gain. However, the significant weight gain shows that this goal was not achieved.

Purpose: Obesity has been implicated in the etiology of benign and malignant prostatic growth due to its influence on metabolic and endocrine changes. Because obesity is an important determinant of serum levels of insulin and leptin (the product of the obesity gene Ob), we investigated the role of obesity and serum levels of insulin and leptin in benign prostatic hyperplasia (BPH) etiology. Materials and Methods: Fasting serum levels of insulin and leptin as well as the body mass index, a measure of overall obesity, and waist-to-hip ratio, an indicator of abdominal obesity, were determined in 200 men newly diagnosed with BPH who were hospitalized for surgery and in 302 randomly selected healthy male subjects from the population in Shanghai, China. Results: A higher waist-to-hip ratio and higher serum insulin were significantly associated with an increased risk of BPH. Relative to men in the lowest waist-to-hip ratio quartile (less than 0.856) those in the highest quartile (greater than 0.923) were at 2.4-fold risk (odds ratio 2.42, 95% confidence interval [CI] 1.34 to 4.37, test for trend p ϭ 0.01). Similarly relative to men in the lowest quartile of insulin (less than 5.87 U. per ml.) those in the highest quartile (greater than 9.76 U. per ml.) were at significantly increased risk (odds ratio 2.47, 95% CI 1.35 to 4.54, test for trend p ϭ 0.009). The effect of insulin on BPH risk was more pronounced in men in low and middle tertiles of the waist-to-hip ratio (odds ratios comparing high to low insulin tertiles 2.8 and 2.7, respectively), while among men in the highest waist-to-hip ratio tertile insulin was not significantly associated with BPH risk. In contrast, we found no significant odds ratio comparing the highest to lowest quartiles of leptin (odds ratio 0.62, 95% CI 0.33 to 1.17) or body mass index (odds ratio 1.64, 95% CI 0.96 to 2.81). Conclusions: Our results suggest that abdominal obesity and increasing serum insulin, and possibly overall obesity but not serum leptin are associated with a higher risk of BPH. Further prospective and laboratory studies are needed to confirm these results and elucidate the underlying mechanisms.

Intra-uterine growth retardation (IUGR), caused by maternal undernutrition or placental insufficiency, is usually associated with disproportionately large reductions in the growth of some fetal organs and tissues (thymus, liver, spleen, thyroid) and impaired cellular development of other tissues (small intestine, secondary wool follicles, skeletal muscle). Growth of other tissues, most notably brain, is relatively unimpaired. In our restudy of postnatal consequences of IUGR in the offspring of prolific ewes, growth-retarded newborn lambs tended to be hypoglycaemic and showed sluggish postnatal engagement of the growth hormone (GH)-insulin-like growth factor (IGF) system. When artificially reared in an optimum environment, low birth weight lambs grew at rates similar to those of normal lambs. However, low birth weight lambs were fatter at any given weight, apparently related to their high energy intakes, especially soon after birth, had low maintenance energy requirements, and limite...

Individuals often perform exercise in the fasted state, but the effects on bone metabolism are not currently known. We compared the effect of an overnight fast with feeding a mixed meal on the bone metabolic response to treadmill running. Ten, physically-active males aged 28 ± 4 y (mean ± 1SD) completed two, counterbalanced, 8 d trials. After 3 d on a standardised diet, participants performed 60 min of treadmill running at 65% V02max on Day 4 following an overnight fast (FAST) or a standardised breakfast (FED). Blood samples were collected at baseline, before and during exercise, for 3h after exercise, and on four consecutive follow-up days (FU1-FU4). Plasma/serum were analysed for the c-terminal telopeptide region of collagen type 1 (P-CTX), n-terminal propeptides of procollagen type 1 (P1NP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), parathyroid hormone (PTH), albumin-adjusted calcium, phosphate, osteoprotegerin (OPG), Cortisol, leptin and ghrelin. Only the P-CTX response was significantly affected by feeding. Pre-exercise concentrations decreased more in FED compared with FAST (47% vs 26%, P < 0.001) but increased during exercise in both groups and were not significantly different from baseline at 1 h post-exercise. At 3 h post-exercise, concentrations were decreased (33%, P < 0.001) from baseline in FAST and significantly lower (P < 0.001) than in FED. P1NP and PTH increased, and OC decreased during exercise. Bone markers were not significantly different from baseline on FU1-FU4. Fasting had only a minor effect on the bone metabolic response to subsequent acute, endurance exercise, reducing the duration of the increase in P-CTX during early recovery, but having no effect on changes in bone formation markers. The reduced duration of the P-CTX response with fasting was not fully explained by changes in PTH, OPQ leptin or ghrelin.

Evidence is growing that appetite regulating peptides such as leptin and ghrelin, but also other hormones including prolactin are altered in alcoholism. The brain pro-opiomelanocortin (POMC) system which has important mediating roles in alcohol intake also has important functions in prolactin regulation and energy homeostasis. Furthermore, it has been demonstrated to be functionally integrated with leptin regulation. The satiety factor leptin seems to be counteracted by the gut-derived peptide ghrelin which increases hunger and food intake. Consequently, the POMC system may have a role in integrating regulation of alcohol effects and these seemingly disparate regulatory systems. The goal of this mini-review is to discuss the results of some recent investigations of the potential interactions of these systems with acute and chronic alcohol responses.

Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.

Aim: To design, manufacture and test a second generation leptin receptor (ObR) agonist glycopeptide derivative. The major drawback to current experimental therapies involving leptin protein is the appearance of treatment resistance. Our novel peptidomimetic was tested for efficacy and lack of resistance induction in rodent models of obesity and appetite reduction.

Background: Chronic kidney disease (CKD) is a significant public health problem that leads to end-stage renal disease (ESRD) with as many as 2 million people predicted to need therapy worldwide by 2010. Obesity is a risk factor for CKD and leptin, the obesity hormone, correlates with body fat mass and markers of renal function. A number of clinical and experimental studies have suggested a link between serum leptin and kidney disease. We hypothesised that variants in the leptin gene (LEP) may be associated with markers of CKD in indigenous black Africans.

Objective: Fructose has been implicated in obesity, partly due to lack of insulin-mediated leptin stimulation and ghrelin suppression. Most work has examined effects of pure fructose, rather than high-fructose corn syrup (HFCS), the most commonly consumed form of fructose. This study examined effects of beverages sweetened with HFCS or sucrose (Suc), when consumed with mixed meals, on blood glucose, insulin, leptin, ghrelin, and appetite. Methods: Thirty lean women were studied on two randomized 2-d visits during which HFCS-and Suc-sweetened beverages were consumed as 30% of energy on isocaloric diets during day 1 while blood was sampled. On day 2, food was eaten ad libitum. Subjects rated appetite at designated times throughout visits. Results: No significant differences between the two sweeteners were seen in fasting plasma glucose, insulin, leptin, and ghrelin (P Ͼ 0.05). The within-day variation in all four items was not different between the two visits (P Ͼ 0.05). Net areas under the curve were similar for glucose, insulin, and leptin (P Ͼ 0.05). There were no differences in energy or macronutrient intake on day 2. The only appetite variable that differed between sweeteners was desire to eat, which had a higher area under the curve the day after Suc compared with HFCS. Conclusion: These short-term results suggest that, when fructose is consumed in the form of HFCS, the measured metabolic responses do not differ from Suc in lean women. Further research is required to examine appetite responses and to determine if these findings hold true for obese individuals, males, or longer periods.

The relationship between leptin and affective disorders is still unknown. We measured free and bound leptin in 13 drug naïve subjects. Leptin did not significantly differ between patients and controls. As part of future studies, it also appears useful to distinguish between free and bound leptin.

Our current understanding of pre-elongation embryo metabolism and its regulation by factors both intrinsic to the embryo and present in its immediate environment is limited mainly to studies in rodents and of ruminant embryos that have been cultured in vitro. Energy metabolism in such embryos is initially low and dependent on oxidative phosphorylation for the generation of ATP. The embryo exhibits substrate preference for carboxylic acids, such as pyruvate, during this period. Glucose uptake is limited initially but increases after compaction, and it is metabolized mostly to lactate. Glucose uptake is facilitated by a number of transporters, but the presence and function of these, and their regulation by growth factors, such as insulin, are not well characterized. Even less is known about the metabolic fate of amino acids and lipids. Approximately 50% of the lipid fraction in the mature oocyte is in the form of triglyceride, much of which is oxidized during fertilization and the ear...