［依頼総説］ヒトは なぜ 太ってしまうのか？ －脂肪細胞科学の進歩が拓く 肥満の病態解明と治療の展望－
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A variety of molecular events provoked in obese adipose tissue considerably contribute to the pathophysiology of life style-related metabolic diseases. Adipocyte-derived hormone leptin controls appetite and fuel homeostasis via the hypothalamus. However, clinical application of leptin for the treatment of obesity-diabetes syndrome has been hampered by the fact that leptin action is deteriorated on a high-fat, westernized diet. In this context, we previously found that the activity of AMP-activated protein kinase (AMPK), a key player of fatty acid oxidation in skeletal muscle, correlates with the increased hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Intracerebroventricular administration of type 4 melanocortin receptor agonist robustly overcomes high fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia in mice, with a concomitant recovery of AMPK activity. On the other hand, glucocorticoid regulates adipose tissue metabolism and body fat distribution, and its action on target tissues depends not only on circulating level but on intracellular concentrations. Locally-enhanced action of glucocorticoid in adipose tissue via the intracellular glucocorticoid reactivating enzyme, 11β-hydrox ysteroid dehydrogenase type 1 (11β-HSD 1) contributes to dysfunction of adipose tissue. Adipose-specific 11β-HSD 1 overexpressors exemplify visceral fat accumulation with insulin resistance, dyslipidemia and hypertension. In contrast, 11β-HSD 1 systemic knockouts as well as adipose-specific 11β-HSD2 transgenics (where intracellular glucocorticoid reactivation was suppressed exclusively in adipose tissue) protect against diabetes and obesity. Exaggerated action of 11β-HSD 1 preferentially in adipose tissue occurs similarly in human obesity. Rodent experiments demonstrate that orallyadministered selective inhibitors of 11β-HSD 1 ameliorate diabetes and arteriosclerosis. These findings offer us the potential for novel therapeutic options in human metabolic diseases.
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