Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance

Mountjoy, Kathleen G.; Caron, Alexandre; Hubbard, Kristina; Shome, Avik; Grey, Angus C.; Sun, Bo; Bould, Sarah; Middleditch, Martin; Pontré, Beau; McGregor, Ailsa L.; Harris, Patricia M.; Kowalczyk, Renata; Brimble, Margaret A.; Botha, Rikus; Tan, Karen; Piper, Sarah; Buchanan, Christina M.; Lee, Syann; Coll, Anthony P.; Elmquist, Joel K.

doi:10.1016/j.molmet.2017.11.008

Cited by 24 publications

(34 citation statements)

References 46 publications

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“…However, a recent study has generated a new mouse model where the cleavage site in ACTH, which is necessary to generate ␣-MSH, has been mutated. By treating these mice with either ␣-MSH or des-acetyl ␣-MSH, it has highlighted the importance of des-acetyl ␣-MSH, by showing it can have an equivalent effect to ␣-MSH in reducing body weight (259).…”

Section: Relative Roles Of ␣-Msh and Its Precursorsmentioning

confidence: 99%

POMC: The Physiological Power of Hormone Processing

Harno

Ramamoorthy

Coll

et al. 2018

Physiological Reviews

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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: Relative Roles Of ␣-Msh and Its Precursorsmentioning

confidence: 99%

POMC: The Physiological Power of Hormone Processing

Harno

Ramamoorthy

Coll

et al. 2018

Physiological Reviews

Self Cite

140

120

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show abstract

“…These findings have recently been challenged by a longer-term study in which both α-MSH and d-α-MSH were genetically deleted from mice, and then individually infused for 14 days at physiological levels into the mouse brain. This study revealed that both peptides could similarly reduce appetite and body weight in male mice 5 . Furthermore, d-α-MSH has been reported to be a more potent agonist of MC4R than α-MSH…”

Section: Discussionmentioning

confidence: 57%

“…S1E). hPSC-derived hypothalamic neurons produce b-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and other POMC-derived peptides…”

Section: Human Hypothalamic Neurons Appropriately Traffic and Secretementioning

confidence: 99%

“…These peptides include desacetyl a-melanocyte stimulating hormone (ACTH(1-13) amide, d-a-MSH(1-13), d-a-MSH), which can also be acetylated to produce a-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Both d-a-MSH and a-MSH stimulate melanocortin receptor 4 (MC4R) in the brain [5][6][7][8] to reduce food intake. POMC is also processed into b-endorphin (b-EP(1-31)) 9,10 which stimulates the µ-opioid receptor to promote analgesia and increased food intake [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

“…Is POMC processing in human hypothalamic neurons regulated by exogenous factors such as leptin ? We found that hPSC-derived hypothalamic neurons trafficked and secreted POMC and its derivatives, and appropriately processed POMC into neuropeptides previously established to regulate energy balance, both in vitro and in vivo. These neuropeptides included b-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). We next developed quantitative assays for POMC-derived peptides and found that acetylated a-MSH was present at substantially (5- to 200- fold) lower concentrations than da-MSH, b-MSH, or b-EP.…”

Section: Introductionmentioning

confidence: 99%

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Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Kirwan

Kay

Brouwers

et al. 2018

Preprint

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Human obesity can result from the aberrant production or processing of proopiomelanocortin (POMC) in hypothalamic neurons, but it is unclear which human POMC-derived peptides are most relevant to body weight regulation. To address this question, we analysed both hypothalamic neurons derived from human pluripotent stem cells (hPSCs) and primary human hypothalamic tissue using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS). In both in vitro-and in vivo-derived samples, we found that POMC was processed into b-melanocyte stimulating hormone (b-MSH), whose existence in the human brain has been controversial. b-MSH and desacetyl a-MSH (d-a-MSH) were produced at roughly equimolar concentrations and in vast excess to acetylated a-MSH (5-to 200-fold), suggesting that the importance of both d-a-MSH and b-MSH to human obesity has been underestimated. Since body weight is sensitive to changes in MSH concentration, we asked whether hPSC-derived hypothalamic neurons could provide mechanistic insights into the processing and secretion of MSH peptides. We found that cultured human hypothalamic neurons appropriately trafficked POMC and its derivatives, and robustly (P<0.0001) secreted them when depolarised. Furthermore, the adipocyte-derived hormone leptin significantly (P<0.01) promoted their production of both d-a-MSH and b-MSH. These results establish hPSC-derived hypothalamic neurons as a model system for studying human-specific aspects of POMC processing that might be therapeutically harnessed to treat obesity.

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Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders

et al. 2020

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Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients. Electronic supplementary material The online version of this article (10.1007/s11892-020-01327-7) contains supplementary material, which is available to authorized users.

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Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance

Cited by 24 publications

References 46 publications

POMC: The Physiological Power of Hormone Processing

POMC: The Physiological Power of Hormone Processing

Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders

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