11β-Hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 2) are involved in the conversion of cortisone (C2755) to cortisol (H0135). 11β-HSD1 is expressed in adipose tissue. Overexpression of the enzyme and increased glutacorticoid levels results in lipid accumulation and an increase in visceral adipocytes [1]. Chronically elevated glucocorticoid levels cause Cushing’s syndrome, a disease caused by excessive cortisol production that triggers obesity, skin darkening, muscle weakness and fatigue. Thus, inhibiting 11β-HSD1 in adipose tissue could prove a viable therapy for treating both this disease and visceral obesity. Acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT1) acts as a key enzyme in the synthesis of triglycerides, the main form of excess calorie storage in fat. DGAT1 is also expressed in adipocytes and overexpression causes increased triglyceride levels. DGAT1-deficient mice exhibit increased insulin (I1507) and leptin (L4146) sensitivity and resistance to diet-induced obesity due to increased energy expenditure [2]. Since dietary fat constitutes 35-45% of energy intake, another therapeutic approach for the treatment of obesity is to inhibit the absorption of fat from the gut. Digestion of dietary fat occurs through the activation of two enzymes: gastric lipases, secreted in the stomach, and pancreatic lipases, secreted in the duodenum. Orlistat (O4139), a pancreatic and gastric lipase inhibitor approved by the FDA in 1999, reduces dietary fat absorption, thereby decreasing hydrolysis of ingested triglycerides [3]. Fatty acids and fatty acid metabolism may influence food intake and metabolic pathways through functions in the brain. Fatty acid synthase (FAS) inhibitors reduce food intake, body weight and body fat by altering the expression of hypothalamic neuropeptides such as NPY/AgRP, MCH (M4135), α-MSH (M2567) and POMC/CART. FAS substrates inhibit the mitochondrial enzyme carnitine palmitoyl transferase I (CPT I), increasing the levels of long chain acyl CoA derivatives levels [4]. Malonyl CoA (M4263) regulates CPT its formation and is regulated by acetyl CoA carboxylase (ACC). Mice deficient in this enzyme produce less malonyl CoA, which in turn increases CPT I and reduces long chain acyl CoA derivative levels, causing an increase in the rate of lipid oxidation [4]. References:1. Stewart, P.M. and Tomlinson, J.W., Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity. Trends Endocrinol. Metab., 13, 94-96 (2002). 2. Yu, Y.-H., et al., Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J. Biol. Chem, 277, 50876-50884 (2002). 3. Finer, N., Pharmacotherapy of obesity. Best Pract. Res. Clin. Endocrinol. Metab., 16, 717-742 (2002). 4. Flier, J.S., Obesity Wars: Molecular progress confronts an expanding epidemic. Cell, 116, 337-350 (2004).
Primary glucocorticoid secreted by the adrenal cortex. It has three times the anti-inflammatory potency of corticosterone but much lower Na2+ retention potency.
Two-chain polypeptide hormone produced by the β-cells of pancreatic islets. Its molecular weight is ~5800 Da. The α and β chains are joined by two interchain disulfide bonds. The α chain contains an intrachain disulfide bond. Insulin regulates the cellular uptake, utilization, and storage of glucose, amino acids, and fatty acids and inhibits the breakdown of glycogen, protein, and fat.
Leptin human >97% (SDS-PAGE), recombinant, expressed in Escherichia coli, lyophilized powder
Leptin is a hormone produced primarily in adipocytes, although leptin mRNA has also been identified in placenta and fetal tissues, gastric tissue and liver. Its primary site of action appears to be on neurons in the hypothalamus that are involved in regulating energy balance, appetite, and body weight. Leptin increases the production of nitric oxide in endothelial cells and stimulates angiogenesis in vitro and in vivo. Human and mouse leptin share ~84% sequence identity.
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