Weak Functional Coupling of the Melanocortin-1 Receptor Expressed in Human Adipocytes

Hoch, Matthias; Hirzel, Estelle; Lindinger, Peter W.; Eberlé, Alex N.; Linscheid, Philippe; Martin, Ivan; Peters, Thomas; Peterli, Ralph

doi:10.1080/10799890802442622

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…MC1R is located primarily in melanocytes of skin and in hair follicles, but is also expressed in macrophages and adipocytes (169). The main role of melanocortin signaling through MC1R is in regulation of pigmentation in the skin and in hair follicles.…”

Section: Melanocortin 1 Receptor (Mc1r)mentioning

confidence: 99%

POMC: The Physiological Power of Hormone Processing

Harno

Ramamoorthy

Coll

et al. 2018

Physiological Reviews

151

120

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Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon.

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Section: Melanocortin 1 Receptor (Mc1r)mentioning

confidence: 99%

POMC: The Physiological Power of Hormone Processing

Harno

Ramamoorthy

Coll

et al. 2018

Physiological Reviews

151

120

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“…However, human adipose tissue only expresses MC1-R to a relevant extent and binding to MC1-R does not induce lipolysis. 8,9 Additional experiments are needed to examine the dose dependence of the MSH/ACTH(4-10) effect. In a pilot experiment with five volunteers and 5 mg MSH/ACTH(4-10) i.n., we could not detect any changes in subcutaneous lipolysis in any of the individuals.…”

Section: Discussionmentioning

confidence: 99%

Intranasal application of the melanocortin 4 receptor agonist MSH/ACTH(4–10) in humans causes lipolysis in white adipose tissue

et al. 2011

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Objective: The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In animals, intracerebroventricular infusion of melanocortin receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ ACTH(4-10) on lipolysis and sympathetic nervous system activity in healthy humans. Design: Healthy normal weight, male volunteers (n ¼ 10) received either 10 mg MSH/ACTH(4-10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion. Results: At 45 min after MSH/ACTH(4-10) administration WAT glycerol concentrations increased by 53.4 ± 19.3% compared with baseline conditions (Po0.05) and remained significantly higher throughout the experiment when compared with placebo (Po0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH(4-10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH(4-10) 569 ± 69% increase to baseline; placebo: 315 ± 64%; Po0.01). Conclusion: Intranasally administered MCR-4 agonist MSH/ACTH 4-10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.

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“…Another important aspect that may limit the melanoma targeting approach with MSH radiopeptides is the expression of MC1R in non-melanoma cell types and tissues as well as the crossreaction of MSH radiopeptides with other MC receptor subtypes such as MC3R, MC4R, and MC5R. For example, MC1R is not only expressed on melanocytes and melanoma cells but also on macrophages, neutrophils, endothelial cells, astrocytes, and adipocytes [173][174][175], although generally to a lesser degree than on melanocytes. Yet, studies in experimental animals have demonstrated that accumulation of MSH radiopeptides in skin tissue (containing melanocytes) surrounding melanoma tumors is very low [79,110] and well tolerated during and after therapy [167].…”

Section: Perspectives and Limitations Of Melanoma Targeting With Msh mentioning

confidence: 99%

Synthetic Peptide Drugs for Targeting Skin Cancer: Malignant Melanoma and Melanotic Lesions

Eberlé

Rout

et al. 2017

CMC

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Peptides play decisive roles in the skin, ranging from host defense responses to various forms of neuroendocrine regulation of cell and organelle function. Synthetic peptides conjugated to radionuclides or photosensitizers may serve to identify and treat skin tumors and their metastatic forms in other organs of the body. In the introductory part of this review, the role and interplay of the different peptides in the skin are briefly summarized, including their potential application for the management of frequently occurring skin cancers. Special emphasis is given to different targeting options for the treatment of melanoma and melanotic lesions. Radionuclide Targeting: α-Melanocyte-stimulating hormone (α-MSH) is the most prominent peptide for targeting of melanoma tumors via the G protein-coupled melanocortin-1 receptor that is (over-)expressed by melanoma cells and melanocytes. More than 100 different linear and cyclic analogs of α-MSH containing chelators for 111In, 67/68Ga, 64Cu, 90Y, 212Pb, 99mTc, 188Re were synthesized and examined with experimental animals and in a few clinical studies. Linear Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH2 (NAP-amide) and Re-cyclized Cys- Cys-Glu-His-D-Phe-Arg-Trp-Cys-Arg-Pro-Val-NH2 (Re[Arg11]CCMSH) containing different chelators at the N- or C-terminus served as lead compounds for peptide drugs with further optimized characteristics. Alternatively, melanoma may be targeted with radiopeptides that bind to melanin granules occurring extracellularly in these tumors. Photosensitizer targeting: A more recent approach is the application of photosensitizers attached to the MSH molecule for targeted photodynamic therapy using LED or coherent laser light that specifically activates the photosensitizer. Experimental studies have demonstrated the feasibility of this approach as a more gentle and convenient alternative compared to radionuclides.

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Weak Functional Coupling of the Melanocortin-1 Receptor Expressed in Human Adipocytes

Cited by 14 publications

References 36 publications

POMC: The Physiological Power of Hormone Processing

POMC: The Physiological Power of Hormone Processing

Intranasal application of the melanocortin 4 receptor agonist MSH/ACTH(4–10) in humans causes lipolysis in white adipose tissue

Synthetic Peptide Drugs for Targeting Skin Cancer: Malignant Melanoma and Melanotic Lesions

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