کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2006736 1066351 2009 4 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Hypothalamic melanocortin signaling and leptin resistance—Perspective of therapeutic application for obesity-diabetes syndrome
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Hypothalamic melanocortin signaling and leptin resistance—Perspective of therapeutic application for obesity-diabetes syndrome
چکیده انگلیسی

The adipocyte-derived hormone, leptin controls feeding behavior, augments fatty acid β-oxidation in the skeletal muscle, attenuates insulin secretion but enhances whole body insulin sensitivity and glucose disposal, thereby serving as a promising therapeutic candidate for the treatment of insulin resistance and dyslipidemia. Along with other researchers, we demonstrated the clinical efficacy and safety of leptin in the treatment of diabetes and dyslipidemia for patients with generalized lipodystrophy. However, the clinical application of leptin has been hampered by the notion that leptin does not fully exert its metabolic effects in human obesity and diet-induced obese rodents. We found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Our data indicate that the activation of skeletal muscle AMPK is mediated by the hypothalamic melanocortin pathway. In fact, intracerebroventricular administration of melanocortin agonist, MT-II in mice robustly overcomes high-fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia, with a concomitant recovery of AMPK activity in skeletal muscle. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the co-administration of melanocortin antagonist, SHU9119 and in the KKAy mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin per se, but was markedly recovered by MT-II. Our data provide evidence for the critical role of the central melanocortin system in leptin-skeletal muscle AMPK axis, and highlight the system as a therapeutic target for leptin insuffciency in obese humans.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Peptides - Volume 30, Issue 7, July 2009, Pages 1383–1386
نویسندگان
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