Glutamate Mediates the Function of Melanocortin Receptor 4 on Sim1 Neurons in Body Weight Regulation

Abstract

SUMMARY The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown and as a result, little is known about the second-order neurons of the MC4R neural pathway. Single minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, disruption of glutamate release selectively from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.

Control of Food Intake and Energy Expenditure by Nos1 Neurons of the Paraventricular Hypothalamus

“…It is likely that both neuropeptides and fast-acting neurotransmitters such as glutamate, the predominant PVH neurotransmitter, contribute to PVH-mediated energy balance. Indeed, Sim1 glutamate signaling is important for overall control of energy balance (Xu et al, 2013). Our DREADD activation studies suggest the possibility that PVH neurons regulate adjacent cells.…”

“…Selective ablation of Sim1 neurons in the CNS, however, lowers oxygen consumption, suggesting a role for Sim1 neurons in the regulation of both food intake and energy expenditure (Xi et al, 2012). Indeed, recent data reveal that glutamatergic signaling in Sim1 neurons contributes to energy expenditure regulation (Xu et al, 2013) neurons provides a potential neuroanatomical mechanism by which sympathetic output may be increased to promote energy expenditure following activation of these PVH neurons. Indeed, activation of Sim1 PVH neurons increases intrascapular temperature overlying BAT.…”

GABAergic Projections from Lateral Hypothalamus to Paraventricular Hypothalamic Nucleus Promote Feeding

“…For immunohistochemistry studies, we used a previously described protocol (Xu et al, 2012). Primary antibody against ␥2 (NB300-190, Novus Biologicals) was used.…”

“…Then RNAscope Multiple Fluorescent Assay, a novel in situ hybridization technique with a unique "double Z" probe design, which greatly increases signal-to-noise ratio and can visualize RNA transcripts at a single molecular level Xu et al, 2013), was used to detect transcripts in the brain (Advanced Cell Diagnostics 3 kcal/g metabolizable energy, 12.5% kcal from fat, Harlan Teklad) from 4-to 5-week-old mice. For 24 h feeding pattern measurements, food intake was determined every hour for 24 h and averaged for comparison between genotypes.…”

Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia

“…Deletion of LepR in GABAergic neurons and disruption of GABA release from LepR neurons both cause obesity (Vong et al, 2011;Xu et al, 2012). However, disruption of GABA release from Pdx1-Cre neurons led to reduced nocturnal feeding and a defective response to NPY-induced hyperphagia associated with blunted growth.…”