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

Butler, Andrew A.

doi:10.1210/en.141.9.3518

Cited by 343 publications

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“…The lack of involvement of MC3-R in GH secretion suggested by our results seems consistent with the reported observation that MC3-R knockout mice do not exhibit aberrant secretion of GH [50, 51]. In contrast, it is interesting to note that null mutations of MC4-R are associated with accelerated linear growth [48], which may suggest the possibility that MC4-R signaling exerts an inhibitory influence on GH secretion.…”

Section: Discussionsupporting

confidence: 91%

“…HS014 is a synthetic selective antagonist of MC4-R [45], and AGRP is a naturally occurring MC3/4-R antagonist acting mostly on MC4-R [46]. MTII is considered a non-selective agonist of MC3/4-R [47], but recent data from MC3-R- or MC4-R-deficient mice suggest that the anorexic action of MTII may be preferentially mediated by MC4-R [48, 49, 50, 51]. γ 1 -MSH can be considered as a selective MC3-R agonist, because MC3-R is the only MC-R subtype that can be activated by low nanomolar concentrations of γ-MSH peptides [52].…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Role of Melanocortin 3 and 4 Receptors in Leptin-Stimulated and Spontaneous Growth Hormone Secretion in Rats

Watanobe¹,

Yoneda

2003

Neuroendocrinology

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It has been reported that the melanocortin 4-receptor (MC4-R) may act downstream of leptin to mediate its effects on food intake and several neuroendocrine functions (the reproductive system, the hypothalamo-pituitary-thyroid axis, and prolactin secretion). However, no previous study examined whether MC4-R mediates leptin stimulatory actions on growth hormone (GH) secretion, or whether MC4-R signaling is involved in spontaneous pulsatile GH release in fed rats. Therefore in this study we examined the involvement of both MC3-R and MC4-R (the predominant MC-R subtypes expressed in the brain) in these two aspects of GH secretion in freely-moving male rats. In both fed and 3-day fasted rats, plasma GH levels were determined every 15 min over 5 h after single intracerebroventricular injections of the following substances or vehicle. Fasting diminished and leptin (0.3 nmol) reinstated the GH pulse amplitude without affecting the pulse frequency. Neither HS014 (1.0 nmol, a selective MC4-R antagonist) nor agouti-related peptide (1.0 nmol, a non-selective MC3/4-R antagonist) was effective in altering leptin-stimulated or spontaneous GH secretion. In addition, neither melanotan-II (1.0 nmol, a non-selective MC3/4-R agonist) nor γ₁-melanocyte-stimulating hormone (10 nmol, a selective MC3-R agonist) affected significantly GH release in fasted rats. We have previously demonstrated that stimulation or blockade of MC4-R, achieved by the same drug dosage as in this study, significantly affect luteinizing hormone and prolactin secretion in rats. The present results thus suggest that neither MC4-R nor MC3-R is involved in leptin-stimulated or spontaneous GH secretion, or at least that the level of MC4-R involvement in GH secretion is much lower than that in luteinizing hormone and prolactin release regulation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Evaluation of the Role of Melanocortin 3 and 4 Receptors in Leptin-Stimulated and Spontaneous Growth Hormone Secretion in Rats

Watanobe¹,

Yoneda

2003

Neuroendocrinology

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“…To date, five MCRs have been described, and they have been shown to have a diverse range of functions. MC1R controls skin pigmentation (Valverde et al 1995), MC3R and MC4R are major contributors to the regulation of food intake and energy homeostasis (Marsh et al 1999, Butler et al 2000, Chen et al 2000 and MC5R is highly expressed during embryogenesis but in adults is believed to be involved in exocrine function (Labbe et al 1994, Chagnon et al 1997, Ogawa et al 2004). MC1,3,4,5R respond to all POMCderived hormones (ACTH and a-, b-and g-MSH) but differ in ligand preference, whereas MC2R responds to ACTH only (Cone et al 1993).…”

Section: Melanocortin 2 Receptor Is a Critical Component Of The Hpa Axismentioning

confidence: 99%

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Novoselova

Jackson

Campbell

et al. 2013

Journal of Endocrinology

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The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R-MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for w20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs. Hypothalamic-pituitary-adrenal axisThe adrenal glands are responsible for releasing different classes of hormones. The inner part of the glands, the medulla, secretes catecholamines under the control of the sympathetic nervous system. The outer part, the cortex, has three functionally distinct layers -the outer zona glomerulosa that secretes aldosterone, the middle zona fasciculata that produces glucocorticoids and the inner zona reticularis that is responsible for the production of adrenal androgens. Production and release of glucocorticoids by the zona fasciculata are tightly regulated by the hypothalamus and pituitary to control

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“…Mice lacking the MC3R are obese but hypophagic. The obese phenotype in these mice is attributed to decreased locomotor activity and aberrant food partitioning into fat [26,27]. There is evidence that on POMC neuron the MC3R functions as a so-called autoreceptor [28].…”

Section: Gpcrs In Hypothalamic Weight Regulationmentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

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

Cited by 343 publications

References 0 publications

Evaluation of the Role of Melanocortin 3 and 4 Receptors in Leptin-Stimulated and Spontaneous Growth Hormone Secretion in Rats

Evaluation of the Role of Melanocortin 3 and 4 Receptors in Leptin-Stimulated and Spontaneous Growth Hormone Secretion in Rats

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

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