Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor

Lu, Dongsi; Willard, Derril H.; Patel, Indravadan R.; Kadwell, Sue H.; Overton, Laurie K.; Kost, Tom; Luther, Michael A.; Chen, Wenbiao; Woychik, Richard P.; Wilkison, William O.; Cone, Roger D.

doi:10.1038/371799a0

Cited by 992 publications

(685 citation statements)

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“…23 Consistent with the MC4-R deficient, 6 POMC-deficient 5 and AgRP overexpressing mouse, 2,4 the obese A y /a mouse displays increased linear growth. We have used the obese A y /a mouse as a model of abnormal melanocortin signalling to study the interaction between obesity, the melanocortin system and somatic growth.…”

Section: Introductionmentioning

confidence: 84%

Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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Objective: Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A y /a) mouse as a model of a perturbed melanocortin system. Design: Adult obese A y /a mice were compared to age-and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation. Results: Obese A y /a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A y /a mice. Obese A y /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A y /a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged. Conclusion: Increased body length in adult obese A y /a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

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Section: Introductionmentioning

confidence: 84%

Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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“…The melanocortin system was implicated in body weight regulation by studies of obese agouti mice (Ay/a) that bear a spontaneous mutation leading to ectopic overexpression of the agouti protein (Miltenberger et al 1997;Salton et al 2000), which exerts an antagonist action at melanocortin receptors (Lu et al 1994). However, as there are five melanocortin receptor subtypes; it remained unclear which were involved in body weight regulation.…”

Section: Animal Models Of Obesitymentioning

confidence: 99%

Relevance of animal models to human eating disorders and obesity

2008

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Background and rationale This review addresses the role animal models play in contributing to our knowledge about the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) and obesity. Objectives Explore the usefulness of animal models in complex biobehavioral familial conditions, such as AN, BN, and obesity, that involve interactions among genetic, physiologic, psychological, and cultural factors. Results and conclusionsThe most promising animal model to mimic AN is the activity-based anorexia rodent model leading to pathological weight loss. The paradigm incorporates reward elements of the drive for activity in the presence of an appetite and allows the use of genetically modified animals. For BN, the sham-feeding preparation in rodents equipped with a gastric fistula appears to be best suited to reproduce the postprandial emesis and the defects in satiety. Animal models that incorporate genes linked to behavior and mood may clarify biobehavioral processes underlying AN and BN. By contrast, a relative abundance of animal models has contributed to our understanding of human obesity. Both environmental and genetic determinants of obesity have been modeled in rodents. Here, we consider single gene mutant obesity models, along with models of obesigenic environmental conditions. The contributions of animal models to obesity research are illustrated by their utility for identifying genes linked to human obesity, for elucidating the pathways that regulate body weight and for the identification of potential therapeutic targets. The utility of these models may be further improved by exploring the impact of experimental manipulations on the behavioral determinants of energy balance.

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“…Importantly, the interaction of the melanocortin peptides with their receptors can be modified by two endogenous protein antagonists, agouti, and agouti-related protein, which are the products of two distinct genes [33,35]. Tissue-specific processing of the pro-opiomelanocortin precursor coupled to tissue-specific expression of MCR subtypes and antagonists has the potential to provide a wide spectrum of physiological responses from these neuropeptides.…”

Section: Introductionmentioning

confidence: 99%