Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat

Central administration of melanocortin 3 and 4 receptor (MC3/4-R) agonists increases energy expenditure, with the hypothalamus commonly held as the primary site of action. It is also clear, however, that MC4-R are expressed in caudal brainstem structures of relevance to the control of energy expenditure. Three experiments investigated whether hindbrain MC-R contribute to the energy expenditure effects of central MC3/4-R agonist treatments; in each, we examined the effect of fourth intracerebroventricular (i.c.v.) administration of a MC3/4-R agonist, MTII (three injections, each separated by 12 h), on uncoupling protein 1 (UCP-1) gene expression in brown adipose tissue (BAT). First, we compared the effects of fourth and third i.c.v. administration of MTII and found that the hindbrain and forebrain treatments were equally effective at elevating UCP-1 mRNA expression in BAT compared with the respective vehicle-treated group results. A second experiment demonstrated that the fourth i.c.v. MTII-induced rise in UCP-1 expression was mediated by sympathetic outflow to BAT by showing that this response was abolished by surgical denervation of BAT. In the third experiment, we showed that chronic decerebrate rats, like their neurologically intact controls, elevated UCP-1 mRNA expression in response to fourth i.c.v. MTII administration. Taken together, the results indicate that: 1) there is an independent caudal brainstem MC3/4-R trigger for a sympathetically stimulated elevation in BAT UCP-1 gene expression, and 2) the MTII-induced rise in UCP-1 expression can be mediated by circuitry intrinsic to the caudal brainstem and spinal cord.