Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain

Mountjoy, Kathleen G.

doi:10.1210/me.8.10.1298

Cited by 681 publications

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“…32 However, the anatomic substrate underlying coordinated food intake control still remained obscure, as scientists in the field lacked key tools to unravel this complex hypothalamic puzzle. Nevertheless, several molecular discoveries in 1990s, especially identification of leptin 5 and melanocortin receptors [33][34][35] implicated other hypothalamic and extra-hypothalamic sites in regulating energy homeostasis.…”

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confidence: 99%

“…69 Of importance, a-MSH acts as an agonist for the melanocortin-4 receptor (MC4-R), 70,77,78 a Gs-proteincoupled receptor distributed in the CNS. 35,79,80 The MC4-R is an established regulator of food intake and body weight, and blockade of this receptor causes obesity. 77,78 An overeating/obesity syndrome is produced, for example, by targeted deletion of the MC4-R 81 and by mutations in the human MC4-R. [82][83][84][85][86][87][88] The importance of MC4-Rs in humans is highlighted by an estimate that 3-5% of the population suffering from morbid obesity may result from MC4-R mutations.…”

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confidence: 99%

“…71,72,96,106,107 The CNS localization of MC4-R has also been examined in the rat and mouse. 35,79,80 For this purpose, radioisotopic in situ hybridization histochemistry has been applied, as high-affinity antibodies against MC4-R protein are unavailable. Notably, nearly all the CNS sites thought to be critical for energy balance regulation display overlapping distributions of melanocortinergic axons and MC4-R mRNA in rodents.…”

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confidence: 99%

“…Notably, nearly all the CNS sites thought to be critical for energy balance regulation display overlapping distributions of melanocortinergic axons and MC4-R mRNA in rodents. 35,79,80 Some of these representative sites are discussed below.…”

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confidence: 99%

“…First, a population of MC4-R-positive PVH neurons may relay inputs from leptin-responsive a-MSH neurons in the Arc to autonomic preganglionic neurons, supporting the implication of melanocortins and MC4-Rs in autonomic regulation. 35,79,80 Secondly, Lu and colleagues provided evidence that melanocortins regulate the hypothalamicpituitary-adrenal axis via MC4-R-positive PVH neurons. 114 The authors demonstrated a subset of PVH cells that coexpresses MC4-R and corticotropinreleasing hormone (CRH) mRNAs.…”

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confidence: 99%

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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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confidence: 99%