Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions

Abstract

Objective: Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood. Design: We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc). Results: Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters. Conclusions: Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.

POMC overexpression in the ventral tegmental area ameliorates dietary obesity

“…However, this may not necessarily be the case with respect to POMC action. A study in rats demonstrated that region-specific expression of AgRP in LH or VMH led to hyperphagia, body weight gain and increased percentage of white adipose tissue (de Backer et al 2010). This study suggests that the LH and VMH both appear to contain melanocortin receptors and they act in concert, suggesting that the anorexic signals coming from a-MSH in these brain regions may be additive to that in the ARC or VTA.…”

A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice

“…Briefly, when leptin activates pro-opiomelanocortin (POMC)-producing neurons in the ARC, α-MSH synthesis and release are stimulated. Alpha-MSH acts on MC4 receptors in the PVN and exerts its anorexigenic effects by activating CRH, TRH and oxytocin neurons and thus inhibits appetite (de Backer et al 2011; Pandit et al 2011). As demonstrated in Fig.…”

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

“…This review, we hope, will serve to identify the questions that still require answers in relation to whether and how relaxin-3 signalling networks interact with the various hypothalamic neural networks and associated chemical messengers currently known to control feeding, metabolism and body weight, including the key NPY/AgRPexpressing and POMC-expressing neurons in the ARC (Schwartz et al, 2000;Cowley et al, 2001;Korner et al, 2001;Williams and Elmquist, 2011) and orexin and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (Sakurai et al, 1998;Willie et al, 2001;Gao and Horvath, 2007;de Backer et al, 2011), which are associated with arousal and reward mechanisms (see e.g. Adamantidis and de Lecea, 2008;Hassani et al, 2010 for a review).…”

“…Fibronectin is a laminar protein that is constitutively secreted by neuronal soma, and thus neurons transduced with rAAV-FIB-R3/I5 secrete R3/I5 locally around the transduced neurons. This approach has been used successfully to alter peptide levels in the hypothalamus and produce effects on body weight (Tiesjema et al, 2007;De Backer et al, 2011).…”