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 . 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 . 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 . 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 . 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 . 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).
Acetyl-CoA Carboxylase (ACC) regulates the metabolism of fatty acids. This enzyme catalzes the formation of Malonyl CoA through the irreversible carboxylation of acetyl CoA. There are two main isoforms of Acetyl-CoA carboxylase expressed in mammals, Acetyl-CoA carboxylase 1 (ACACA) and Acetyl-CoA carboxylase 2 (ACACB). ACACA has broad tissue distribution but is enriched in tissues critical for fatty acid sythesis such as adipose tissue. ACACB is enriched in tissues such as skeletal muscle and heart that are critical for fatty acid oxidation.
The Acetyl-CoA Carboxylase enzymes are activated by citrate, glutamate, and dicarboxylic acids and negatively regulated by long and short chain fatty acyl CoAs. Because of thier roles in fatty acid metabolism and oxidation, ACACA and ACACB are therapeutic targets for treating obesity and metabolic syndrome disorders.
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 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.
Coenzyme A functions as an acyl group carrier, acetyl-CoA. Malonyl Coenzyme A is a coenzyme A derivative that is utilized in fatty acid and polyketide synthesis and in the transport of α-ketoglutarate across the mitochondrial membrane. Malonyl CoA is formed by the Acetyl CoA Carboxylase-mediated carboxylation of acetyl CoA. Malonyl-CoA is exclusively used as the extender unit in the synthesis of bacterial aromatic polyketides.
Hormone that stimulates melanogenesis; facilitates learning and memory; affects inflammatory and immune responses and peripheral nerve regeneration. Pituitary hormone which causes darkening skin pigmentation from amphibians to humans. In mammals, it can also have behavioral effects on learning, attention, and memory.1