The adipocyte-derived
hormone,
leptin controls feeding behavior, augments
fatty acid beta-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 KKA(y) 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.