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.