Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

Glucocorticoids have a major role in determining adipose tissue metabolism and distribution. 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADPH-dependent enzyme highly expressed in the liver and adipose tissue. In most intact cells and tissues it functions as a reductase (to convert inactive cortisone to active cortisol). It has been hypothesized that tissue-specific deregulation of cortisol metabolism may be involved in the complex pathophysiology of the metabolic syndrome (MS) and obesity. Transgenic mice overexpressing 11betaHSD1 in adipose tissue develop obesity with all features of the MS, whereas 11betaHSD1-knockout mice are protected from both. The bulk of evidences points to an overexpression and increased activity of 11betaHSD1 also in human adipose tissue. However, 11betaHSD1 seems to adjust local cortisol concentrations independently of its plasma levels. In Cushing's syndrome, 11betaHSD1 is downregulated and may not be responsible for the abdominal fat depots; it also undergoes downregulation in response to weight loss in human obesity. The nonselective 11betaHSD1 inhibitor carbenoxolone improves insulin sensitivity in humans, and selective inhibitors enhance insulin action in diabetic mice liver, thereby lowering blood glucose. Thus, 11betaHSD1 is now emerging as a modulator of energy partitioning and a promising pharmacological target to treat the MS and diabetes.

Os glicocorticóides (GC) têm papel importante na determinação do metabolismo e da distribuição do tecido adiposo. A 11beta-hidroxisteróide desidrogenase tipo 1 (11betaHSD1) é uma enzima dependente de NADPH, altamente expressa nos tecidos hepático e adiposo. Em muitas células e tecidos intactos, ela funciona como redutase (convertendo cortisona em cortisol). Postula-se que uma desregulação tecido-específica do cortisol estaria envolvida na complexa fisiopatologia da síndrome metabólica (SM) e obesidade. Ratos que super-expressam 11betaHSD1 no tecido adiposo desenvolvem obesidade e todas as características da SM, enquanto ratos knockout para 11betaHSD1 são protegidos. Evidências apontam para uma super-expressão e aumento da atividade 11betaHSD1 também no tecido adiposo humano. Entretanto, a 11betaHSD1 parece ajustar a concentração local de cortisol independente da sua concentração sérica. Na síndrome de Cushing, a expressão da 11betaHSD1 é regulada para baixo, não devendo ser a causa dos depósitos de gordura visceral; em obesos, há também regulação para baixo em resposta à perda de peso. A carbenoxolona, um inibidor não seletivo da 11betaHSD1, melhora a sensibilidade insulínica em humanos e inibidores seletivos aumentam a sensibilidade insulínica hepática e melhoram o controle glicêmico em ratos diabéticos. Assim, a 11betaHSD1 está emergindo como um modulador da compartimentalização de energia e um alvo farmacológico promissor para o tratamento da SM e do diabetes.

The role of AMP kinase in diabetes.

Type 2 diabetes is characterized by abnormal metabolism of glucose and fat, due in part to resistance to the actions of insulin in peripheral tissues. If untreated it leads to several complications such as blindness, kidney failure, neuropathy and amputations. The benefit of exercise in diabetic patients is well known and recent research indicates that AMP activated protein kinase (AMPK) plays a major role in this exercise related effect. AMPK is considered as a master switch regulating glucose and lipid metabolism. The AMPK is an enzyme that works as a fuel gauge, being activated in conditions of high energy phosphate depletion. AMPK is also activated robustly by skeletal muscle contraction and myocardial ischaemia, and is involved in the stimulation of glucose transport and fatty acid oxidation produced by these stimuli. In liver, activation of AMPK results in enhanced fatty acid oxidation and decreased production of glucose, cholesterol, and triglycerides. The two leading diabetic drugs namely, metformin and rosiglitazone, show their metabolic effects partially through AMPK. These data, along with evidence from studies showing that chemical activation of AMPK in vivo with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) improves blood glucose concentrations and lipid profiles, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes and other metabolic disorders.

Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts

Mitochondrial biogenesis is known to accompany adipogenesis to complement ATP and acetyl-CoA required for lipogenesis. Here, we demonstrated that mitochondrial proteins such as ATP synthase alpha and beta, and cytochrome c were highly expressed during the 3T3-L1 differentiation into adipocytes. Fully-differentiated adipocytes showed a significant increase of mitochondria under electron microscopy. Analysis by immunofluorescence, cellular fractionation, and surface biotinylation demonstrated the elevated levels of ATP synthase complex found not only in the mitochondria but also on the cell surface (particularly lipid rafts) of adipocytes. High rate of ATP (more than 30 micrometer) synthesis from the added ADP and Pi in the adipocyte media suggests the involvement of the surface ATP synthase complex for the exracellular ATP synthesis. In addition, this ATP synthesis was significantly inhibited in the presence of oligomycin, an ATP synthase inhibitor, and carbonyl cyanide m-chlorophenylhydrazone (CCCP), an ATP synthase uncoupler. Decrease of extracellular ATP synthesis in acidic but not in basic media further indicates that the surface ATP synthase may also be regulated by proton gradient through the plasma membrane.