Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling

Chai, Biaoxin; Li, Ji Yao; Zhang, Weizhen; Wang, Hui; Mulholland, Michael W.

doi:10.1016/j.peptides.2009.03.006

Cited by 41 publications

(33 citation statements)

References 38 publications

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“…[31][32][33] In addition, melanocortin system has been recently shown to modulate insulin signaling via c-Jun N-terminal kinase activity. 34 Impairment of POMC protein synthesis was associated, in our patient, with a Cushingoid phenotype and severe metabolic alterations despite the normal hypothalamic-pituitary-adrenal function. This sits easily with the observation that POMC-null mice are hypersensitive to adverse effects of glucocorticoids in terms of development and accumulation of fat mass, hyperglycemia and insulin resistance.…”

Section: Discussionmentioning

confidence: 56%

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

et al. 2012

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Rare mutations in several genes have a critical role in the control of homeostatic mechanisms such as food-intake, energy balance and glucose metabolism. In this study, we performed a mutational screening in a 58-year-old woman presenting early-onset type 2 diabetes and central obesity. The entire coding regions of MC4R, MC3R, HNF1A, GCK and POMC (pro-opiomelanocortin) genes were analyzed by direct sequencing. A new missense mutation was identified within the POMC gene signal peptide sequence, resulting in a heterozygous substitution of an arginine for a glycine at codon 15 (p.A15G) that was excluded in 300 healthy normal weight controls. The mutation segregated in the family and was associated with overweight, type 2 diabetes, hypertension and coronary heart disease in the carriers. Functional studies demonstrated that POMC protein was not detectable in b-TC3 cells transfected with A15G-POMC vector as well as in their culture media, despite POMC mRNA levels were comparable for amount and stability to those of wild-type-transfected cells. In silico RNA folding prediction indicated that the mutation gives rise to a different RNA secondary structure, suggesting that it might affect translation and protein synthesis. To the best of our knowledge, this is the first report addressing the functional consequences of a mutation in the signal peptide of POMC. These findings further support the hypothesis that POMC-derived peptides might have a role in the control of peripheral glucose metabolism and suggest that disruption of central POMC secretion might represent an additional link between type 2 diabetes and obesity.

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Section: Discussionmentioning

confidence: 56%

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

et al. 2012

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“…Moreover, the increased POMC gene expression may be related to the JNK inhibition. Chai et al (2009) found that the alteration of POMC receptor activation (melanocortin-4 receptor) could participate in the regulation of JNK activity in HEK293 cells. Although p38 MAPK and ERK signalling can regulate appetite in mammals (Morikawa et al, 2004;Kim et al, 2010), acute acetate treatment did not affect the level of phosphorylation of p38 MAPK and ERK proteins.…”

Section: Discussionmentioning

confidence: 99%

Acetate induces anorexia <i>via</i> up-regulating the hypothalamic pro-opiomelanocortin (<i>POMC</i>) gene expression in rabbits

Liu¹,

Liu²,

Fu³

et al. 2017

J. Anim. Feed Sci.

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“…For the JNK pathway, NDP-α-MSH does-dependently inhibits JNK in HEK293 cells stably expressing MC4R [78]. AMPK phosphorylation level was demonstrated to be decreased by MC4R activation with MTII in PVH neurons and NDP-α-MSH stimulation in MC4R-transfected HEK293T cells [56, 74].…”

Section: Intracellular Signaling Pathways Of Neural Mcrsmentioning

confidence: 99%

Biased signaling at neural melanocortin receptors in regulation of energy homeostasis

Yang

Tao

2017

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

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The global prevalence of obesity highlights the importance of understanding on regulation of energy homeostasis. The central melanocortin system is an important intersection connecting the neural pathways controlling satiety and energy expenditure to regulate energy homeostasis by sensing and integrating the signals of external stimuli. In this system, neural melanocortin receptors, melanocortin-3 and -4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy homeostasis. Recently, multiple intracellular signaling pathways and biased signaling at neural MCRs have been discovered, providing new insights into neural MCR signaling. This review attempts to summarize biased signaling including biased receptor mutants (both naturally occurring and lab-generated) and biased ligands at neural MCRs, and to provide a better understanding of obesity pathogenesis and new therapeutic implications for obesity treatment.

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Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling

Cited by 41 publications

References 38 publications

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity

Acetate induces anorexia <i>via</i> up-regulating the hypothalamic pro-opiomelanocortin (<i>POMC</i>) gene expression in rabbits

Biased signaling at neural melanocortin receptors in regulation of energy homeostasis

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