Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain
melanocortin (MC) system is important in
leptin signaling and maintenance of energy balance. Although
leptin or MC receptor insensitivity has been proposed to be associated with
obesity, the present study compared central
leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced
obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of
leptin and of the MC agonist
melanotan-II caused comparable increases in plasma
ACTH and
corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of
leptin and
melanocortins. In the DIO prediction study, anorexigenic efficacy of
melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]
alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals,
leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma
leptin, liver weight, and abdominal adiposity, the latter being correlated to
insulin resistance. Thus, differences in
leptin but not MC signaling might underlie DIO,
visceral obesity, and
insulin resistance.