Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats

The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obes ity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that fo od intake- independent mechanisms contribute to development of obesity indu ced by pharmacological blockade of MC receptors in the brain and that chang es in hypothalamic neuropeptidergic systems known to regulate weight gain [ i. e., corticotropin-releasing hormone (CRH), cocaine- amphetamine- related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] w ould trigger this effect. Relative to vehicle- treated controls, third intr acerebroventricular (i3vt) administration of the MC receptor antagonist SHU 9119 to rats for 11 d doubled food and water intake (toward the end of trea tment) and increased body weight (similar to 14%) and fat content (similar to 90%), hepatic glycogen content (similar to 40%), and plasma levels of ch olesterol (similar to 48%), insulin (similar to 259%), glucagon (similar to 80%), and leptin (similar to 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair- feeding of i3vt SHU9119- treated animals to i3vt vehicle- treated controls normalized plasma levels of insul in, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (similar to 31%) and leptin (similar to 1 04%) and body fat content (similar to 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair fe eding, but rather were more pronounced. None of the effects found can be ex plained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i. e., CART, POMC, and NPY) and paravent ricular (i. e., CRH) hypothalamus. The results indicate that reduced activi ty of the CNS MC pathway promotes fat deposition via both food intake- depe ndent and -independent mechanisms.