Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency

Gui, Yijun; Dahir, Naima S.; Wu, Yanan; Downing, Griffin; Sweeney, Patrick; Cone, Roger D.

doi:10.1016/j.celrep.2023.113188

Cited by 8 publications

(9 citation statements)

References 49 publications

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“…We first tested the effect of the long-term adipostatic hormone leptin, a hormone produced by the adipose tissue in proportion to fat stores 28 . Given that Mc3r -/- mice display late-onset weight gain and hyperleptinemia 7,13 , these mice should theoretically exhibit leptin resistance. In contrast, Mc3r -/- mice also exhibited increased anorectic sensitivity to leptin; low doses of leptin, which otherwise did not affect food intake in WT mice, showed robust anorectic response in male Mc3r -/- mice (Fig 3A).…”

Section: Resultsmentioning

confidence: 99%

“…The MC3R is expressed in nearly all AgRP neurons 10 , which project widely throughout the CNS 11 . For example, the defective fasting-induced activation of AgRP neurons essential for the stimulation of food intake, observed in the global Mc3r -/- mouse, is also seen in mice with deletion of the Mc3r exclusively from the AgRP neurons 13 . Thus, the Agrp-iCre;Mc3r fl/fl was used to study the role of MC3R expression in the AgRP neurons in the hypersensitivity to anorectic hormones described here.…”

Section: Resultsmentioning

confidence: 99%

“…For example, MC3R is essential in promoting normal compensatory re-feeding and neuroendocrine responses to fasting 7–10 . MC3R accomplishes this by regulating GABA release onto MC4R neurons from presynaptic MC3R expressed on AgRP neurons 9,12 , and by controlling the activation of AgRP neurons 13 . Further, MC3R is requisite for normal growth 5,14 and reproductive function, with mutations leading to reduced linear growth and lean mass and late onset of puberty in mice and humans 15 .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

Dahir,

Gui,

et al. 2023

Preprint

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The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response inMc3r-/-mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

Dahir,

Gui,

et al. 2023

Preprint

Self Cite

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show abstract

“…We first tested the effect of the long-term adipostatic hormone leptin, a hormone produced by the adipose tissue in proportion to fat stores ( 28 ). Given that Mc3r –/– mice display late-onset weight gain and hyperleptinemia ( 7 , 13 ), these mice should theoretically exhibit leptin resistance. In contrast, Mc3r –/– mice also exhibited increased anorectic sensitivity to leptin; low doses of leptin, which otherwise did not affect food intake in WT mice, showed robust anorectic activity in male Mc3r –/– mice ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…For example, MC3R is essential in promoting normal compensatory refeeding and neuroendocrine responses to fasting ( 7 , 8 , 10 , 12 ). The MC3R accomplishes this by regulating GABA release onto MC4R neurons from presynaptic MC3R expressed on agouti-related protein (AgRP) neurons ( 9 , 12 ) and controlling the activation of AgRP neurons ( 13 ). Furthermore, the MC3R is requisite for normal growth ( 4 , 5 ) and reproductive function, with mutations leading to reduced linear growth, lean mass, and late onset of puberty in mice and humans ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice

Dahir,

Gui,

et al. 2024

Journal of Clinical Investigation

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Functional redundancy between glucocorticoid and mineralocorticoid receptors in mature corticotropin‐releasing hormone neurons protects from obesity

Liu,

Lin,

Najam

et al. 2024

Obesity

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ObjectiveHere, we aimed to investigate the role of glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) in the regulation of energy homeostasis.MethodsWe used three mouse models with simultaneous deletion of GRs and MRs in either forebrain neurons, the paraventricular nucleus, or corticotropin‐releasing hormone (CRH) neurons and compared them with wild‐type controls or isolated knockout groups. In addition to body weight, food intake, energy expenditure, insulin sensitivity, fat/lean mass distribution, and plasma corticosterone levels, we also performed transcriptomic analysis of CRH neurons and assessed their response to melanocortinergic stimulation.ResultsSimilar to global double‐knockout models, deletion of GRs and MRs specifically in mature CRH neurons resulted in obesity. Importantly, the latter was accompanied by insulin resistance, but not increased plasma corticosterone levels. Transcriptomic analysis of these neurons revealed upregulation of several genes involved in postsynaptic signal transduction, including the Ptk2b gene, which encodes proline‐rich tyrosine kinase 2. Knockout of both nuclear receptors leads to upregulation of Ptk2b in CRH neurons, which results in their diminished responsiveness to melanocortinergic stimulation.ConclusionsOur data demonstrate the functional redundancy of GRs and MRs in CRH neurons to maintain energy homeostasis and prevent obesity. Simultaneous targeting of both receptors might represent an unprecedented approach to counteract obesity.

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Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency

Cited by 8 publications

References 49 publications

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice

Functional redundancy between glucocorticoid and mineralocorticoid receptors in mature corticotropin‐releasing hormone neurons protects from obesity

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