Leptin and Beyond: Actors in Cancer

Leptin is a 16-kDa multifunctional, neuroendocrine peptide hormone secreted by adipocytes in proportion to total adipose tissue mass, known to control food intake, energy homeostasis, immune response, and reproductive processes [...]

Protective Role of Plasminogen Deficiency in Non-Alcoholic Fatty Liver Disease and Glucose Dysmetabolism

Obesity is global health problem with 40% of the world population being classified as overweight (BMI > 25) and 13% as obese (BMI > 30). Obesity drives chronic metabolic inflammation leading to metabolic syndrome, cardiovascular disease, fatty liver disease, Type II diabetes, and certain cancers. A documented clinical manifestation of obesity is perturbed and dysregulated hemostatic system leading to a procoagulant and anti-fibrinolytic state that ultimately results in an increased risk of thrombosis. Previous work suggested that clotting system components thrombin and fibrin engage in reciprocal mechanisms and contribute to the development of obesity. Specifically, we have shown that fibrin accumulates within obese adipose tissue and liver of obesity patients and mice challenged with a high fat diet (HFD) and colocalizes with macrophages, a key driver of inflammation in obesity. Despite the fact that obesity is known to be linked to an impaired fibrinolytic system, a potential functional contribution of fibrinolytic proteases to the development of obesity and associated downstream diseases has been understudied. Here, we tested the hypothesis that elimination of the fibrinolytic protease plasminogen would increase HFD-driven fibrin deposition and exacerbate macrophage accumulation and subsequent weight gain and obesity-associated pathologies. Contrary to our hypothesis, plasminogen-deficient (Plg-) mice gained as much weight as the Plg+ mice after 20 weeks on HFD. However, whereas the liver mass of HFD-challenged Plg+ mice was significantly higher than that of low fat diet (LFD)-fed mice, the livers of HFD-fed Plg- mice had a mass comparable to LFD-fed mice. HFD-fed Plg- mice had reduced hepatocellular damage, measured by plasma ALT activity, as well as reduced hepatosteatosis, measured by hepatic triglyceride content and liver histology, compared to HFD-fed Plg+ mice. Circulating cholesterol levels in HFD-fed Plg -/- mice were comparable to LFD-fed Plg- mice, while it was significantly elevated in HFD-fed Plg+ mice. While the epididymal white adipose tissue mass was higher in HFD-fed Plg- mice compared to HFD-fed Plg+ mice, the brown adipose tissue mass was comparable. However, there was an upregulation of uncoupling protein-1 (UCP-1) expression BAT of HFD-fed Plg- mice. Glucose clearance was more efficient in HFD-fed Plg- mice compared to HFD-fed Plg+ mice in a glucose tolerance test. Collectively, our data suggest that plasmin(ogen) contributes to HFD-induced fatty liver disease and glucose dysmetabolism. Disclosures No relevant conflicts of interest to declare.

Activation of the adipocyte CREB/CRTC pathway in obesity

Obesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function.

Body Composition of Chronic Kidney Disease Patients

With accelerated muscle proteolysis, a decrease in muscle mass is evident in chronic kidney disease (CKD) patients. This eventually leads to nutritional disturbance that for a long has been mostly attributed to malnutrition. This predisposes patients to premature morbidity and mortality. Assessing body composition, thus, becomes vital. In this cross-sectional study, CKD patients (n = 47) of stages 2, 3a, 3b and 4 were assessed for their lean tissue mass, adipose tissue mass and overhydration by body composition monitor. Lean tissue index and fat tissue index were calculated as lean tissue mass and adipose tissue mass in kilogram divided by patients’ height in square meters. Patients were assessed for their handgrip strength (HGS) by Jamar hydraulic hand dynamometer, and also for their 7-day diet history. Mean lean tissue index of CKD patients was 11.73 ± 2.49 kg/m2. About 34 (72.3%) out of 47 patients were below the reference value of lean tissue index. A significant difference in lean tissue index (P = 0.03) was observed at various stages. Patients at stage 4 had the lowest lean tissue index. Lean tissue was significantly (P = 0.03) low in patients consuming protein <0.6 gm/kg/day. All 47 patients had less than normal HGS values. Patients’ mean fat tissue index was 14.86 ± 6.18 kg/m2 and had water retention with a mean overhydration of 1.47 ± 2.12 L. CKD patients were malnourished with a significant low lean tissue index. Dietary protein intake and HGS of these patients were positively associated with lean tissue index.

Step-Defined Physical Activity Is Associated With Weight Loss and Changes in Body Composition and Fat Distribution in Response to Diet Interventions: The POUNDS Lost Trial

Objectives To examine whether objectively measured physical activity (PA) is associated with weight loss and changes in body composition and fat distribution in response to weight-loss diet interventions. Methods This study included 535 overweight or obese participants randomly assigned to 4 weight-loss diets varying in macronutrient intake with physical activity measured objectively with pedometers in the POUNDS Lost trial. The associations of step defined PA or the changes in PA with the changes in obesity measurements including body weight (BW), waist circumference (WC), body fat composition assessed by the dual-energy X-ray absorptiometry (DEXA) scans, body fat distribution assessed by the computed tomography (CT) were examined at the 6 and 24 months. We also examined whether the associations were modified by diet interventions. Results The increase of step-defined PA was significantly predictive of weight loss and decrease in all measurements of body fat composition and distribution in response to diet interventions over 24 months (P &lt; 0.0001 for all). We also observed significant inverse associations of changes in PA with changes in BW (P &lt; 0.0001), WC (P &lt; 0.0001), body fat composition (P &lt; 0.05 for total fat, total lean, total fat mass %, and trunk fat %) and fat distribution (P &lt; 0.05 for total adipose tissue mass (TAT), visceral adipose tissue mass (VAT), deep subcutaneous adipose tissue mass (DSAT)) from baseline to 6 months, when the maximum weight loss was achieved. Dietary fat or protein intake modified the associations between changes in PA and changes in body weight and waist circumference over 24 months; greater reduction in these measures was observed in participants with high-fat or low-protein diets than those in the low-fat or high-protein diets (P interaction &lt; 0.05 for all). Conclusions Our results indicate that objectively measured PA is inversely related to the changes in body weight, body composition, and fat distribution in response to weight-loss diets, and such relation is more evident in people with high-fat or low-protein diets. Funding Sources The study was supported by grants from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and Tulane Research Centers of Excellence Awards.

Proto-oncoprotein Zbtb7c and SIRT1 repression: implications in high-fat diet-induced and age-dependent obesity

Zbtb7c is a proto-oncoprotein that controls the cell cycle and glucose, glutamate, and lipid metabolism. Zbtb7c expression is increased in the liver and white adipose tissues of aging or high-fat diet-fed mice. Knockout or knockdown of Zbtb7c gene expression inhibits the adipocyte differentiation of 3T3-L1 cells and decreases adipose tissue mass in aging mice. We found that Zbtb7c was a potent transcriptional repressor of SIRT1 and that SIRT1 was derepressed in various tissues of Zbtb7c-KO mice. Mechanistically, Zbtb7c interacted with p53 and bound to the proximal promoter p53RE1 and p53RE2 to repress the SIRT1 gene, in which p53RE2 was particularly critical. Zbtb7c induced p53 to interact with the corepressor mSin3A-HADC1 complex at p53RE. By repressing the SIRT1 gene, Zbtb7c increased the acetylation of Pgc-1α and Pparγ, which resulted in repression or activation of Pgc-1α or Pparγ target genes involved in lipid metabolism. Our study provides a molecular target that can overexpress SIRT1 protein in the liver, pancreas, and adipose tissues, which can be beneficial in the treatment of diabetes, obesity, longevity, etc.

Azoxymethane-Induced Colorectal Cancer Mice Treated with a Polyphenol-Rich Apple Extract Show Less Neoplastic Lesions and Signs of Cachexia

Obesity is considered a risk factor for the development of colorectal cancer. In rodents, high-fat (HF) diets are able to increase the formation of azoxymethane (AOM)-induced polyps. Polyphenol-rich apple extracts have antioxidant and anti-inflammatory activities and may induce an amelioration of the manifestations of colorectal cancer. Twenty-seven male Crl:CD-1 mice received AOM during four weeks and were subsequently divided into three groups fed a HF diet (n = 9 each group): a non-supplemented group, a second group supplemented with apple extract at 1%, and a third group supplemented with the same apple extract at 1.5%. Energy metabolism and the respiratory quotient were not affected by the supplementation with the apple extract. Although body weight was not affected by the treatment, the mice supplemented with the apple extract showed less signs of cachexia than the non-treated mice. In the intestine, the mice supplemented with the apple extract showed lower sucrase, dipeptidyl-peptidase IV, and aminopeptidase N activities, and less intestinal lesions (aberrant crypt foci and polyps). Administration of a polyphenol-rich apple extract reduces the number of neoplastic lesions in mice with AOM-induced colorectal cancer and contributes to preserve adipose tissue mass.

Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways

SUMMARYThe STAT (Signal Transducers and Activators of Transcription) family of transcription factors contributes to adipocyte development and function. STAT5A and STAT5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH). Studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. We have generated a mouse model lacking both STAT5 genes specifically in adipocytes (STAT5AKO). Notably, both sexes of STAT5AKO mice have increased inguinal adipose tissue without any changes in gonadal fat mass. However, both depots exhibit substantial differences in fat cell size. Study of STAT5AKO mice also have revealed that GH’s ability to induce insulin resistance is dependent upon STAT5 in adipocytes, but its ability to reduce adipose tissue mass is STAT5 independent. Additional observations, which were not predicted, indicate that the causes and regulation of increased fat mass in STAT5AKO mice are sex- and depot-dependent.

Epigallocatechin-3-Gallate Reduces Visceral Adiposity Partly through the Regulation of Beclin1-Dependent Autophagy in White Adipose Tissues

Epigallocatechin-3-gallate (EGCG) is a primary bioactive phytochemical in green tea. Its therapeutic potential in metabolic diseases has been reported; however, the molecular mechanisms of the anti-obesity effect of EGCG have not been fully elucidated. In this study, we examined the effects of EGCG on lipid metabolism and autophagy in adipose tissue. After 8 weeks of high-fat diet feeding, mice were treated with EGCG (20 mg/kg/day) for 2 weeks to test in vivo anti-obesity effects of EGCG. EGCG treatment improved glucose tolerance and caused body weight loss. Interestingly, reduced adipose tissue mass was more prominent in visceral compared to subcutaneous white adipose tissue. Mechanistically, EGCG treatment increased autophagic flux in white adipose tissue through the AMP-activated protein kinase-mediated signaling pathway. Adipocyte-specific knockout of Beclin1 mitigated the effects of EGCG on visceral adipose tissue mass and glucose tolerance, indicating that the anti-obesity effect of EGCG requires Beclin1-dependent autophagy. Collectively, our data demonstrated that EGCG has anti-obesity effects through the upregulation of Beclin1-dependent autophagy and lipid catabolism in white adipose tissue (WAT).