Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity

Abstract

Pharmacological and genetic studies have suggested that melanocortin-4 receptor (MC4R) signaling in the paraventricular nucleus of hypothalamus (PVN) regulates appetite and energy balance. However, the specific role of MC4R signaling in PVN neurons in these processes remains to be further elucidated in normally developed animals. In the present study, we employed RNA interference to determine whether MC4R knockdown in the PVN modulates food intake and body weight in adult rats. Adeno-associated viral (AAV) vectors encoding short hairpin RNAs targeting MC4R (AAV-shRNA-MC4R) were generated to induce MC4R knockdown in the PVN. By in situ hybridization, we detected a high-level expression of Dicer, a key enzyme required for shRNA-mediated gene silencing, along the entire rostrocaudal extent of the PVN. Bilateral injection of AAV-shRNA-MC4R vectors into the PVN of the adult rat resulted in significant and specific reduction of MC4R mRNA expression. Animals with MC4R knockdown exhibited an increase in food intake and excessive body weight gain when exposed to a high-fat diet. Our results provide evidence that AAV-mediated silencing of MC4R on PVN neurons promotes hyperphagia and obesity in response to the dietary challenge in the adult animal.

Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: Effects on food intake and body weight

“…Among the involved signals is a-melanocyte-stimulating hormone (a-MSH), a 13 amino acid acylated neuropeptide produced in the arcuate nucleus of the hypothalamus (Harris and Lerner, 1957). a-MSH is a potent inducer of satiation and energy expenditure (Cone et al, 2001;Barsh and Schwartz, 2002;Morton et al, 2006;Valassi et al, 2008), activating the melanocortin receptor type 4 (MC4R), which are highly expressed in the hypothalamic paraventricular nucleus (PVN) and some other hypothalamic and extrahypothalamic brain regions (Gantz et al, Mountjoy et al, 1994;Kishi et al, 2003;Balthasar et al, 2005;Garza et al, 2008). Central MC4R appears, thus, as an attractive pharmacological target for treatment of overeating and obesity.…”

Increased feeding and body weight gain in rats after acute and chronic activation of RXFP3 by relaxin-3 and receptor-selective peptides

“…When high leptin levels are detected by these neurons, POMC is processed to produce a-melanocyte-stimulating hormone (a-MSH), which is released and binds the melanocortin receptor 4 (MCR4), through which anorexigenic pathways are activated (Gao and Horvath, 2007). MCR4 is abundant in the ARC, PVN, and lateral and dorsomedial hypothalamus (Garza et al, 2008).…”

Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression

“…Centrally, leptin signaling is relayed mainly through the hypothalamic melanocortin system and MC4R-expressing neurons. Mc4r expression is widespread in the brain (10,11), with high levels in the hypothalamus and brainstem, areas involved in energy homeostasis (12). The hypothalamus governs metabolism through complex neuroendocrine regulations.…”