Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

Girardet, Clémence; Mavrikaki, Maria; Stevens, Joseph R.; Miller, Courtney A.; Marks, Daniel L.; Butler, Andrew A.

doi:10.1038/srep44444

Cited by 21 publications

(35 citation statements)

References 64 publications

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“…The response of NAG neurons to hypocaloric conditioning is restored in LoxTB Mc3r mice in which hypothalamic expression was rescued using Nkx2.1-Cre (Girardet et al, 2017). This study also observed that restoring FAA in LoxTB Mc3r mice is independent of improvements in adiposity.…”

Section: Is There a Role For Mc3rs In Appetite Regulation?mentioning

confidence: 99%

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

et al. 2017

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Melanocortin neurons conserve body mass in hyper- or hypo-caloric conditions by conveying signals from nutrient sensors into areas of the brain governing appetite and metabolism. In mice, melanocortin-3 receptor (MC3R) deletion alters nutrient partitioning independently of hyperphagia, promoting accumulation of fat over muscle mass. Enhanced rhythms in insulin and insulin-responsive metabolic genes during hypocaloric feeding suggest partial insulin resistance and enhanced lipogenesis. However, exactly where and how MC3Rs affect metabolic control to alter nutrient partitioning is not known. The behavioral phenotypes exhibited by MC3R-deficient mice suggest a contextual role in appetite control. The impact of MC3R-deficiency on feeding behavior when food is freely available is minor. However, homeostatic responses to hypocaloric conditioning involving increased expression of appetite-stimulating (orexigenic) neuropeptides, binge-feeding, food anticipatory activity (FAA), entrainment to nutrient availability and enhanced feeding-related motivational responses are compromised with MC3R-deficiency. Rescuing Mc3r transcription in hypothalamic and limbic neurons improves appetitive responses during hypocaloric conditioning while having minor effects on nutrient partitioning, suggesting orexigenic functions. Rescuing hypothalamic MC3Rs also restores responses of fasting-responsive hypothalamic orexigenic neurons in hypocaloric conditions, suggesting actions that sensitize fasting-responsive neurons to signals from nutrient sensors. MC3R signaling in ventromedial hypothalamic SF1(+ve) neurons improves metabolic control, but does not restore appetitive responses or nutrient partitioning. In summary, desensitization of fasting-responsive orexigenic neurons may underlie attenuated appetitive responses of MC3R-deficient mice in hypocaloric situations. Further studies are needed to identify the specific location(s) of MC3Rs controlling appetitive responses and partitioning of nutrients between fat and lean tissues.

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Section: Is There a Role For Mc3rs In Appetite Regulation?mentioning

confidence: 99%

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

et al. 2017

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“…In summary, the current results indicate that MC3R signaling in AgRP +ve neurons appears to have an inhibitory role in regulating feeding behavior. When compared with previous studies using this model (2,(29)(30)(31), there appears to be functional divergence between MC3Rs expressed on first-order and second-order neurons of the central nervous melanocortin system. MC3Rs expressed on first-order AgRP +ve neurons are inhibitory.…”

Section: Discussionmentioning

confidence: 71%

“…Ventral tegmental area MC3Rs support the expression of feeding-related motivational responses during situations of energy deficit (29). MC3R signaling in Nkx2.1 +ve neurons in the hypothalamus also supports behavioral adaptation to energy deficit (30). MC3R signaling in the nervous system thus appears to be predominantly orexigenic, particularly during situations of energy deficit.…”

Section: Discussionmentioning

confidence: 97%

Melanocortin‐3 Receptors Expressed on Agouti‐Related Peptide Neurons Inhibit Feeding Behavior in Female Mice

Girardet

Marks

Butler

2018

Obesity

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Objective Activation of hypothalamic agouti‐related peptide expressing (AgRP)+ve neurons during energy deficit is a negative valence signal, rapidly activating food‐seeking behaviors. This study examined the roles of melanocortin‐3 receptors (MC3Rs) coexpressed in a subpopulation of AgRP+ve neurons. Methods AgRP‐MC3R mice expressing MC3Rs selectively in AgRP+ve neurons were generated by crossing AgRP‐IRES‐Cre mice with LoxTBMc3r mice containing a “loxP‐STOP‐loxP” sequence in the 5′ untranslated region. Body weight, body composition, and feeding behavior were assessed during ad libitum and time‐restricted feeding conditions. Results In females, food intake of AgRP‐IRES‐Cre+ve (n = 7) or AgRP‐IRES‐Cre‐ve (n = 9) mice was not significantly different; these mice were therefore pooled to form the “control” group. Female AgRP‐MC3R mice exhibited lower food intake (25.4 ± 2.4 kJ/12 h; n = 6) compared with controls (35.3 ± 1.8 kJ/12 h; n = 16) and LoxTBMc3r mice (32.1 ± 2.1 kJ/12 h; n = 9) in the active phase during the dark period. Food intake during the rest phase (lights on) when mice consume less food (9‐10 kJ) was normal between genotypes. Body weight and composition of AgRP‐MC3R and LoxTBMc3r mice were similar, suggesting compensatory mechanisms for reduced calorie intake. Remarkably, AgRP‐MC3R mice continued to consume less food during refeeding after fasting and time‐restricted feeding. Conclusions MC3Rs expressed on AgRP+ve neurons appear to exert a strong inhibitory signal on hypothalamic networks governing feeding behavior.

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“…However, exactly where and how MC3Rs affects metabolic control to alter nutrient partitioning is not known. Interestingly, the impact of Mc3r deficiency on feeding behavior when food is freely available is very minor; however, responses to hypocaloric conditioning are compromised featuring partial insulin resistance and enhanced lipogenesis [112]- [114]. Apart from metabolic features, Mc3r null mice develop other phenotypes such as high susceptibility to salt-sensitive hypertension [115] and, due to expression of MC3R outside the brain, increased immune response resulting in a complex phenotype (reviewed in [116]).…”

Section: The Role Of Mc3r In Metabolic Regulationmentioning

confidence: 99%

Pathophysiology of melanocortin receptors and their accessory proteins

Novoselova

Chan

Clark

2018

Best Practice & Research Clinical Endocrinology & Metab

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The melanocortin receptors (MCRs) and their accessory proteins (MRAPs) are involved in regulation of a diverse range of endocrine pathways. Genetic variants of these components result in phenotypic variation and disease. The MC1R is expressed in skin and variants in the MC1R gene are associated with ginger hair color. The MC2R mediates the action of ACTH in the adrenal gland to stimulate glucocorticoid production and MC2R mutations result in familial glucocorticoid deficiency (FGD). MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated. MRAPs have been shown to modulate the function of MCRs and genetic variants in MRAPs are associated with diseases including FGD type 2 and potentially early onset obesity. This review provides an insight into recent advances in MCRs and MRAPs physiology, focusing on the disorders associated with their dysfunction.

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Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

Cited by 21 publications

References 64 publications

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

Melanocortin‐3 Receptors Expressed on Agouti‐Related Peptide Neurons Inhibit Feeding Behavior in Female Mice

Pathophysiology of melanocortin receptors and their accessory proteins

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