Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area

Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390-9127
The Journal of Comparative Neurology (Impact Factor: 3.23). 12/2012; 520(18):4168-83. DOI: 10.1002/cne.23145
Source: PubMed


The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of the hypothalamus and regulates multiple processes including food intake, reward behaviors, and autonomic function. By using a mouse line in which green fluorescent protein (GFP) is expressed under control of the MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology, and retrograde tracing techniques. We found that LHA MC4R-GFP neurons coexpress neurotensin as well as the leptin receptor but do not coexpress other peptide neurotransmitters found in the LHA including orexin, melanin-concentrating hormone, and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP- sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens, and spinal cord, and only limited number of neurons project to the nucleus of the solitary tract and parabrachial nucleus. Our findings provide new insights into MC4R signaling in the LHA and its potential implications in homeostatic regulation of body energy balance. J. Comp. Neurol. 4168-4183, 2012. © 2012 Wiley Periodcicals, Inc.

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Available from: Kevin W Williams, Feb 11, 2014
    • "They documented the IR with the HOMA model and found that centrally, there were increases in hypothalamic paraventricular nucleus (PVH) glucose and insulin levels, as well as melanocortin 4 receptor (MC4R) protein levels but not MC3R or insulin receptors . The involvement of the PVH in the AAR had been demonstrated previously and has long been recognized to be involved in chemoreflex, cardiac sympathetic afferent reflex, baroreflex and now, apparently the AAR (Shi et al. 2012, Xiong et al. 2012, 2014, Cui et al. 2013, Ding et al. 2013, 2015). Involvement of the PVH MC4Rs was shown when low-dose-capsaicininduced AAR output was boosted by PVH-injected HS024 (MC4R agonist) and reduced by SHU9119 (MC3/4R antagonist) (Ding et al. 2015). "
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    ABSTRACT: Although the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) has received nearly all the investigation of the innervation of the tissue, there has long been immunochemical evidence of sensory nerve-associated peptides in neural fibers innervating WAT such as peptide substance P (Fredholm, 1985) and later another sensory-nerve associated peptide CGRP was discovered in laboratory rat WAT (Skofitsch and Jacobowitz, 1985). More recently, direct anatomical evidence (tract tracing) for WAT sensory innervation occurred labeling the pseudounipolar neurons of the dorsal root ganglia (DRG) after application of the retrograde neural tract tracer True Blue into laboratory rat WAT (Fishman and Dark, 1987) showing the first order sensory neurons that project rostrally via unknown circuits presumably providing sensory inflow to the brain from the DRGs multisynaptically. With the advent of transneuronal tract tracing where entire circuits could be labeled within the same animal, we were able to trace the terminal fields of the sensory nerve circuits from WAT (Song et al., 2009) and from BAT (Song and Bartness, 2007, Vaughan and Bartness, 2012) using the H129 strain of herpes simplex virus-1 made possible because H129 travels only in an anterograde manner; thus, only spinal sensory nerves would be labeled given there are not parasympathetic (PSNS) innervation of adipose tissue. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Acta Physiologica
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    • "An endogenous antagonist exists: agouti-related protein (AgRP). AgRP and α-MSH are both synthesized in a distinct population of neurons within the arcuate nucleus (ARC) of the hypothalamus and project throughout the brain[1,8910. Targeted disruption of the mouse MC4R gene leads to an obese phenotype; many types of MC4R mutations lead to severe obesity and hyperphagia in humans[11], suggesting that MC4R signaling in the brain is critical for the regulation of central energy homeostasis to control body energy balance, energy expenditure , and food intake. In humans, mutations in the MC4R gene are found in up to 5% of individuals with morbid obesity[12]. "
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    ABSTRACT: Background: The melanocortin 4 receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards. Methods: We examined the expression levels of D2R and MC4R by dual immunofluorescence histochemistry in hypothalamic regions and in the bed nucleus of the stria terminalis (BNST), the central amygdala, and the ventral tegmental area of transgenic mice expressing enhanced green fluorescent protein under the control of the D2R gene. Results: In the hypothalamic area, significant coexpression of MC4R and D2R was observed in the arcuate nucleus. We observed a significant coexpression of D2R and MC4R in the BNST, which has been suggested to be an important site for food reward. Conclusion: We suggest that MC4R and D2R function in the hypothalamus for control of energy homeostasis and that within the brain regions related with rewards, such as the BNST, the melanocortin system works synergistically with dopamine for the integration of food motivation in the control of feeding behaviors.
    Full-text · Article · Jan 2015
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    • "However, our results indicate that it is unlikely that loss of MC4R signaling in D1R neurons mediates the increased sensitivity to HFD observed in MC4R-null mice. Future studies are warranted to determine the neural substrates through which MC4Rs affect consumption of HFD, such as the LHA, which expresses MC4Rs and is an additional site of reward processing (Cui et al. 2012b). Previous pharmacological studies have shown that intra- NAc infusion of the MC3/4R antagonist SHU9119 significantly blocks most behavioral effects of cocaine including locomotor sensitization (Hsu et al. 2005). "
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    Full-text · Article · Jun 2013 · Genes Brain and Behavior
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