A mouse model for a partially inactive obesity-associated human MC3R variant

Lee, Bonggi; Koo, Jashin; Jun, Joo Yun; Гаврилова, Оксана; Lee, Yong-Jun; Seo, Arnold Y.; Taylor-Douglas, Dezmond C.; Adler-Wailes, Diane C.; Chen, Faye; Gardner, Ryan; Koutzoumis, Dimitri N.; Kazemzadeh, R Sherafat; Roberson, Robin; Yanovski, Jack A.

doi:10.1038/ncomms10522

Cited by 28 publications

(37 citation statements)

References 58 publications

(81 reference statements)

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“…This was at least partially due to an alteration of mesenchymal stem cell fate, which seemed favored towards differentiation to triglyceride-accumulating adipocytes instead of osteoblasts. Additionally, unlike most other obese mouse models, MC3R hDM/hDM mice had greater circulating adiponectin, which we then also observed in samples from MC3R hDM/hDM humans [4]. It is possible that increased serum adiponectin may stimulate mesenchymal stem cell mobilization into adipose tissue, resulting in less bone mass [76] with shorter femur and reduced trabecular bone mineral density of MC3R hDM/hDM mice.…”

Section: Human Studiesmentioning

confidence: 52%

“…To clarify the role the MC3R T6K+V81I variant plays in obesity and metabolism, our group generated two novel homozygous knock-in mouse models [4] where we replaced the murine Mc3r with either human wildtype (hWT) MC3R ( MC3R hWT/hWT ) or the human doublemutant (hDM) T6K+V81I MC3R ( MC3R hDM/hDM ). The MC3R hWT/hWT mice were phenotypically normal, while the MC3R hDM/hDM mice exhibited greater fat mass (Figure 2) and feeding efficiency with reduced fat-free mass – results similar to those found in the Mc3r knockout mouse.…”

Section: Human Studiesmentioning

confidence: 99%

“…Despite their greater adiposity, MC3R hDM/hDM mice also showed reduced obesity-associated metabolic dysfunction [4]. MC3R hDM/hDM mice had well-maintained insulin sensitivity with similar serum glucose, triglycerides, cholesterol, free-fatty acid and corticosterone concentrations when compared to the non-obese MC3R hWT/hWT mice.…”

Section: Human Studiesmentioning

confidence: 99%

“…MC3R hDM/hDM mice had well-maintained insulin sensitivity with similar serum glucose, triglycerides, cholesterol, free-fatty acid and corticosterone concentrations when compared to the non-obese MC3R hWT/hWT mice. MC3R hDM/hDM mice exhibited higher circulating leptin that appeared related to their increased adiposity rather than to the presence of leptin resistance, since suppression of food intake by leptin appeared normal [4]. Additionally, MC3R hDM/hDM mice demonstrated increased bone marrow fat, along with decreased crown-rump length and femur length.…”

Section: Human Studiesmentioning

confidence: 99%

“…One hypothalamic protein, the melanocortin 3 receptor (MC3R), is believed to be one of the many factors important for regulating energy homeostasis; however its role is not completely understood. Moreover, recent evidence suggests that MC3R may regulate metabolism not only via central but also via peripheral actions [4–6]. Herein we briefly review MC3R structure and function, discuss the polymorphisms and mutations identified in humans, and summarize the in vitro , murine, and human studies examining their putative effects.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

Demidowich¹,

Jun²,

Yanovski³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Inactivating mutations in the melanocortin 3 receptor (Mc3r) have been described as causing obesity in mice, but the physiologic effects of MC3R mutations in humans have been less clear. Here we review the MC3R polymorphisms and mutations identified in humans, and the in vitro, murine, and human cohort studies examining their putative effects. Some, but not all, studies suggest that the common human MC3R variant T6K+V81I, as well as several other rare, function-altering mutations, are associated with greater adiposity and hyperleptinemia with altered energy partitioning. In vitro, the T6K+V81I variant appears to decrease MC3R expression and therefore cAMP generation in response to ligand binding. Knockin mouse studies confirm the T6K+V81I variant increases feeding efficiency and the avidity with which adipocytes derived from bone or adipose tissue stem cells store triglycerides. Other MC3R mutations occur too infrequently in the human population to make definitive conclusions regarding their clinical effects.

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Section: Human Studiesmentioning

confidence: 52%

Section: Human Studiesmentioning

confidence: 99%

Section: Human Studiesmentioning

confidence: 99%

Section: Human Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

Demidowich¹,

Jun²,

Yanovski³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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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GPCR’s and Endocrinology

Gorvin

2022

Comprehensive Pharmacology

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A mouse model for a partially inactive obesity-associated human MC3R variant

Cited by 28 publications

References 58 publications

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

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

GPCR’s and Endocrinology

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