Differential Role of Melanocortin Receptor Subtypes in Cachexia

Abstract

Animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a sparing of lean body mass (LBM) and burning of fat, and an overall decrease in basal metabolic rate. In contrast, cachexia is a pathological state of malnutrition associated with many infections and chronic diseases, wherein appetite is diminished concomitant with an increase in metabolic rate, and a relative wasting of LBM. In previous studies, we demonstrated that anorexia and weight loss in mouse cachexia models induced by lipopolysaccharide (LPS) administration and by tumor growth are ameliorated by central melanocortin-4 (MC4) receptor (MC4-R) blockade. In contrast to the results seen with MC4 blockade, melanocortin-3 (MC3) receptor knockout (MC3-RKO) mice show illness-induced anorexia and weight loss with LPS administration and with cytokine administration, and they have similar decreases in mobility. Both MC3-RKOs and MC4-RKOs have an intact corticosterone response and fever with LPS injection. In tumor models, we show that MC4-RKO mice resist the loss of LBM brought about by tumor growth, whereas MC3-RKO animals show enhanced tissue wasting. These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia.

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

“…In accordance with our data, an effect of MC3‐R on cancer‐induced cachexia has been reported but not on food intake 30. In tumour‐bearing mice, blockade of MC3‐R increased tumour‐induced cachexia, but it did not modify the anorexigenic effect of cancer 30.…”

The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)

“…Therefore, we proposed that peripheral signals produced during illness activate POMC neurons and thereby increase signaling at MC4 receptors. This predicts that the loss of an auto-inhibitory 'brake' on these neurons, as provided by the MC3R, would enhance cachexia in our models, and this what was found [26]. This model also predicts that MC3R agonists should stimulate feeding, and therefore provide a potential therapeutic target to dampen the effects of cachexia.…”

“…Obviously, the fact that the MC3R is also expressed in the ventromedial hypothalamus (VMH) and more than 30 other brain nuclei in the rat [29] as well as in multiple in peripheral tissues [5,16,17] indicates that this is unlikely to be the only role for this receptor. Nonetheless, our previous studies demonstrated that MC3RKO mice were highly susceptible to cachexia during acute and chronic disease, whereas the MC4RKO mice were resistant to cachexia [26,28]. Therefore, we proposed that peripheral signals produced during illness activate POMC neurons and thereby increase signaling at MC4 receptors.…”

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

“…Mc4r are involved in the anorexia associated with lipopolysaccaride and tumor-induced cachexia [20,25,27,35,36]. To determine if antagonism of Mc4r by PG932 can attenuate illness behavior, we assessed food intake and spontaneous physical activity of mice treated with LPS (Fig.…”

“…Cytokine stimulation of proopiomelanocortin neurons in the hypothalamus is thought to have an important role in weight loss associated with chronic illness [33]. Administration of antagonists of the Mc3r and Mc4r, or genetic blockade of Mc4r, are effective at ameliorating cachexia induced by bacterial endotoxin (lipopolysaccharide, or LPS) or cancer in several animal models [25,27,35,36].…”