Role of melanocortinergic neurons in feeding and the agouti obesity syndrome

Abstract

Dominant alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors, we identified cyclic melanocortin analogues that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and A(Y) mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.

Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

“…More recently, the application of pharmacological studies and molecular biology techniques has identified α-MSH as an important hypothalamic satiety signal [11,28]. The MC3R is expressed in both central and peripheral tissues and although the physiological role for this MCR has not yet been identified, it is the MCR with the greatest affinity for γ-MSH and it appears to mediate some aspects of the central control of blood pressure [32].…”

“…The MC4R is expressed in virtually all brain regions and the distribution of this MCR in the CNS is both different and wider than that of the MC3R. Furthermore, the MC4R has been implicated in feeding behaviors and weight homeostasis [9,11,43]. Targeted deletion of the MC5R gene has implicated that this MCR subtype is involved in the coordination of exocrine gland function [6].…”

a-MSH enhances activity-based anorexia

“…The brain MC system comprises of (a) proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) and nucleus of the solitary tract [9,17]; (b) agouti-related protein (AGRP) neurons in the ARC [4,20] and (c) melanocortin 3 and 4 receptors (MCRs), which are widely distributed throughout the brain [16,36,39]. Stimulation of the MC system by intracerebroventricular (icv) infusion of a-melanocyte-stimulating hormone (a-MSH) or its analogs results in hypophagia [13,46]. a-MSH infusion raises metabolic rate, increases sympathetic nerve traffic to brown adipose tissue and stimulates lipolysis in ob/ob mice and wildtype rats [15,23].…”

“…Furthermore, a-MSH treatment influences HPA axis activity by increasing adrenocorticotropin (ACTH) and corticosterone release in rats [10,48]. These effects can be antagonized by treatment with the competitive MC antagonist SHU9119 [1,13,41]. Furthermore, the inverse agonist AGRP (83-132) increases food intake, decreases oxygen consumption and reduces capacity of brown adipose tissue to expend energy [19,32,43].…”

Screening for melanocortin-4 receptor mutations in a cohort of Belgian morbidly obese adults and children

“…Leptin also inhibits the orexigenic neurons expressing neuropeptide Y (NPY) and AGRP. 2,4,5 The importance of MC4R in the etiology of obesity was first demonstrated through the inactivation of this receptor in mice. Mice lacking the receptor develop a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia and hyperglycemia.…”