Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

Abstract

SummaryLoss of appetite and cachexia is an obstacle in the treatment of chronic infection and cancer. Proinflammatory cytokines released from activated immune cells and acting in the central nervous system (CNS) are prime candidates for mediating these metabolic changes, potentially affecting both energy intake as well as energy expenditure. The effect of intravenous administration of two proinflammatory cytokines, IL-1β (15 µg/kg) and TNF-α(10 µg/kg) on food and water intake, locomotor activity, oxygen consumption (VO 2 ), and respiratory exchange ratio (RER) was evaluated. The two cytokines elicited a comparable decrease in food intake and activated similar numbers of cells in the paraventricular nucleus of the hypothalamus (PVH), a region that plays a critical role in the regulation of appetite and metabolism (determined via expression of the immediate early gene, c-fos). However, only IL-1β reduced locomotion and RER, and increased VO 2 , while TNF-α was without effect. To examine the role of the melanocortins in mediating IL-1β-induced metabolic changes, animals were pretreated centrally with a melanocortin receptor antagonist, HS014. Pretreatment with HS014 blocked the effect of IL-1β on food intake and RER at later time points (beyond 8hr post injection), as well as the hypoactivity and increased metabolic rate. Further, HS014 blocked the induction of Fos-ir in the PVH. These data highlight the importance of the melanocortin system, particularly within the PVH, in mediating a broad range of metabolic responses to IL-1β.

Molecular and neuroendocrine mechanisms of cancer cachexia

“…In accordance with the existance of an adrenal-mediated effect, adrenalectomy suppressed IL1B-induced muscle atrophy, whilst glucocorticoid treatment was enough to promote muscle atrophy (Braun et al 2011). Interestingly, in spite of muscle wasting induced by cancer, uremia, or LPS, as well as IL1B-induced anorexia is suppressed by MC4R blockade (Marks et al 2001, 2003, Wisse et al 2001, Cheung et al 2008, Whitaker & Reyes 2008), MC4R-knockout animals are not saved from body lean mass loss after central infusion of IL1B (Braun et al 2011), these findings indicate that different neuronal circuits are involved in the CNS modulation of muscle catabolic programs and that the hypothalamus is crucial for induction and maintenance of the main symptoms of cancer cachexia.…”

Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis

“…Central melanocortin signaling is not necessary for IL-1-induced muscle atrophy Pharmacologic blockade of the type 4 melanocortin receptor (MC4R) prevents IL1-induced anorexia (Whitaker and Reyes, 2008) and attenuates lean mass loss in experimental cachexia (Marks et al, 2001;Wisse et al, 2001;Cheung et al, 2005). Furthermore, the MC4R is critical to the CNS regulation of many other facets of metabolism (Nogueiras et al, 2007;PerezTilve et al, 2010).…”

Immune-to-brain signaling and substrates of altered behavior during inflammation

“…[79] However; antagonizing the action of α-melanocyte stimulating hormone, which is produced by neurons of the arcuate nucleus of the hypothalamus, on central melanocortin receptors has been found to alleviate hypophagia after the peripheral administration of either IL-1β or LPS from 8 h onwards. [80,81] These findings indicate that the overall role of the arcuate hypothalamus is to counter reduced food intake, even though activation of some of its composing neurons does seem to play a role in sustained inflammation-associated hypophagia.…”