title: [Energy homeostasis regulated by an adipocyte-derived hormone--mechanism of leptin resistance and role of hypothalamic melanocortin signaling].
abstract: A variety of metabolic/molecular changes in obese adipose tissue considerably contribute to the pathophysiology of life style-related diseases. Fat cell-derived hormone leptin controls appetite and energy homeostasis, thereby enhancing whole body insulin sensitivity. However, clinical application of leptin for the treatment of obesity/metabolic syndrome has been hampered by the fact that leptin does not fully exert its beneficial metabolic impact on prevalent forms of obesity. In an attempt to elucidate underlying mechanism of leptin resistance in obesity, we found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) tightly parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Actually, intracerebroventricular administration of melanocortin agonist MT-II robustly overcomes high fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia in mice, with a concomitant recovery of AMPK activity in skeletal muscle, thereby highlighting the system as a therapeutic target for leptin resistance. In this context, type 4 melanocortin receptor is a promising drug target for the treatment of obesity/metabolic syndrome.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D020738:Leptin / Q000502:physiology*; D053486:Melanocortins / Q000502:physiology*; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020738:Leptin; D053486:Melanocortins