(+)-Z-Bisdehydrodoisynolic Acid Enhances Basal Metabolism and Fatty Acid Oxidation in Female Obese Zucker Rats

We have previously reported that the synthetic estrogen, (+)-Z-bisdehydrodoisynolic Acid [(+)-Z-BDDA], attenuated weight gain and cardiovascular risk in obese rodents. To determine if these antiobesity effects were attributed to changes in basal metabolism, we assessed indirect calorimetry and metabolic profile in female obese Zucker (OZR) rats provided (+)-Z-BDDA (0.0002% food admixture) for 11 weeks. Similar to our previous findings, (+)-Z-BDDA reduced weight gain and improved lipid and glucose homeostasis in OZR rats. Furthermore, resting energy expenditure was increased by (+)-Z-BDDA, as evident by heat production and oxygen consumption. We also observed a marked reduction in respiratory quotient (RQ) along with a corresponding induction of hepatic AMPK in rodents provided (+)-Z-BDDA. Collectively, these findings indicate that (+)-Z-BDDA partially attenuated obesity and associated pathologies through increased resting energy expenditure and fatty acid utilization. Further investigation is required to fully elucidate the mechanisms involved as well as to determine the potential therapeutic implications for (+)-Z-BDDA on obesity and its related pathologies

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3-null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3-null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3-null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets. Introduction Body adipose mass is regulated by matching caloric intake to caloric expenditure over time. The CNS is a critical site where signals of adipose stores are sensed and where appropriate changes in intake and/or expenditure are produced. Over the past decade, a number of proteins have been implicated in the process of sensing peripheral fuel status and the effector mechanisms that defend peripheral adipose mass (1). While most of these proteins are neurotransmitters, receptors, or intracellular signaling molecules, recent data indicate an important role for a unique family of proteins called syndecans. Syndecans are ubiquitous cell surface heparan sulfate proteoglycans (HSPGs; proteins with covalently attached, highly acidic sugar chains), unique in their ability to bind many extracellular peptides, such as hormones and growth factors. Syndecans are found on almost every cell type (2) but are differentially expressed depending on the tissue type. Evidence for the involvement of syndecans in the control of energy balance comes from mice that overexpress syndecan-1 (3). Despite using the pan-selective cytomegalovirus promoter enhancer, Reizes and colleagues showed that mice overexpressing syndecan-1 express transgenic syndecan-1 in a highly unique and circumscribed pattern including expression in regions of the hypothalamus that have long been linked to energy balance regulation, such as the paraventricular nucleus (3, 4). Quite unexpectedly, these mice also show a profound, maturity-onset obesity and type 2 diabetes (3). Although such data indicate a potential role for syndecans in the CNS control of energy balance, syndecan-1 is not normally expressed in the CNS. However, other members of the syndecan family are expressed in the CNS and, most nota

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3–null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3–null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3–null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets

Adaptation of Intestinal and Bile Acid Physiology Accompany the Metabolic Benefits Following Ileal Interposition in the Rat

© 2017, Springer Science+Business Media, LLC. Purpose: Ileal interposition recapitulates many of the metabolic improvements similar to Roux-en-Y gastric bypass. We aimed to determine whether the metabolic improvements seen following ileal interposition were conferred solely by the interposed segment by examining changes in neighboring intestinal segments as well as the composition of the bile acid pool. Materials and Methods: Adult male rats were treated with either sham or ileal interposition surgeries. Glucose tolerance tests, body composition analysis, polymer chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were done after the surgeries. Results: This study showed that ileal interposition improved glucose tolerance and enhanced both fasting and glucose-stimulated GLP-1 secretion in diabetic rats. Total bile acid pool was similar between groups but the composition favored glycine-conjugation in rats with ileal interposition. Insulin secretion was highly correlated with the 12-alpha-hydroxylase index of activity. The interposed ileum exhibited an increase in mRNA for preproglucagon and peptide YY; however, the bile acid transporter, apical sodium bile acid transporter, was dramatically reduced compared to sham rats. The interposed segment becomes jejunized in its new location as indicated by an increase in Glut2 and Pepck mRNA, genes predominantly synthesized within the jejunum. Conclusion: Ileal relocation alone can significantly alter the bile acid pool to favor a more insulin-sensitive metabolism in association with intestinal wide alterations in mRNA for a variety of genes. Ileal interposition may confer metabolic improvement via both the interposed segment and the associated intestinal changes in all segments of the intestine, including the colon

Sensitivity to the Anorectic Effects of Leptin Is Retained in Rats Maintained on a Ketogenic Diet despite Increased Adiposity

BACKGROUND: Rats maintained on a ketogenic diet (KD; 80% fat, 15% protein, 5% carbohydrate) have increased adiposity and leptin as compared to chow-fed controls (CH; 16% fat, 19% protein, 65% carbohydrate), although body weights and daily caloric intakes do not differ. METHODS: Rats maintained on a KD or CH were assessed for responsivity to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) leptin. Hypothalamic gene expression was evaluated to determine the effects of KD on proopiomelanocortin (POMC) mRNA expression and components of the leptin-signaling system. RESULTS: Caloric intake by KD rats was decreased at a lower dose of i.p. leptin (100 μg) than was required to reduce intake by CH rats (leptin, caloric intake was reduced in KD rats as compared to intake following i.p. saline; p < 0.05). In a separate experiment to evaluate responsivity to i.c.v. leptin, the minimal dose of leptin required to significantly reduce 24-hour caloric intake did not differ between the groups. In the arcuate nucleus, POMC mRNA was elevated after a lower dose of i.c.v. leptin in KD rats (5 μg) than was required to increase POMC mRNA expression in CH rats (15 μg) or reduce caloric intake in either group. Finally, evaluation of the level of phosphorylated STAT3 (pSTAT3) in the arcuate and SOCS3 mRNA in the hypothalamus revealed significantly more pSTAT3-positive cells and increased SOCS3 mRNA expression at baseline for KD rats, compared to CH, neither of which was further increased following i.p. leptin administration. CONCLUSION: These data demonstrate that despite increased adiposity, leptin and markers of leptin resistance, responsivity to the anorectic effects of exogenous leptin is retainable during maintenance on a KD