A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse

Butler, Andrew A.; Ra, Kesterson; Khong, Kathy; Mj, Cullen; Ma, Pelleymounter; DeKoning, Jenefer; Baetscher, Manfred; Rd, Cone

doi:10.1210/endo.141.9.7791

Cited by 550 publications

(345 citation statements)

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“…Decreased PeVN somatostatin mRNA expression in obese A y /a mice therefore may be secondary to abnormal MC4-R signalling. Since the MC3-R null mouse does not display increased body length, 58,59 this suggests that it is abnormal signalling through the MC4-R, not the MC3-R, that increases linear growth.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Abnormalities of the somatotrophic axis in the obese agouti mouse

et al. 2005

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“…The obesity phenotype of the MC4-R null mouse strongly supports a role for this receptor in obese states [28]. Transgenic mice lacking the MC3-R have not clarified the role of the MC3-R to the same extent [7,13]. Similarly, since α-MSH [57] and AgRP [50] bind to both MC3-and MC4-Rs, studies of the interactions between the melanocortin system and the HPT axis are unable to establish which receptor subtype(s) is involved.…”

Section: The Melanocortin System and The Hpt Axismentioning

confidence: 99%

“…However, to date, detailed analyses of the HPT axis in these models are limited. MC3-R deficient mice have normal plasma T4 levels [7,13], although plasma thyroid hormones in either MC4-R-null [28] or AgRP overexpressing [23,50] have not been described. In a recent study, transgenic mice lacking all POMC-derived peptides had reduced plasma T4 [11], consistent with a stimulatory effect of POMC-derived peptides such as α-MSH on the HPT axis.…”

Section: The Hpt Axis In Models Of An Abnormal Melanocortin Systemmentioning

confidence: 99%

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

et al. 2006

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“…107 Although MC3-R-deficient mice are not hyperphagic, they do display an increased fat mass. 144,145 Clearly, more studies are needed to identify the MC3-Rpositive sites responsible for energy balance regulation. Nevertheless, these observations indicate the existence of anatomically and functionally divergent melanocortinergic CNS pathways.…”

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confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse

Cited by 550 publications

References 0 publications

Abnormalities of the somatotrophic axis in the obese agouti mouse

Abnormalities of the somatotrophic axis in the obese agouti mouse

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

Body weight is regulated by the brain: a link between feeding and emotion

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