Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

Demidowich, Andrew P.; Jun, Joo Yun; Yanovski, Jack A.

doi:10.1016/j.bbadis.2017.03.018

Cited by 32 publications

(29 citation statements)

References 86 publications

(146 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IKKα and IKKβ, the critical activators of the NF-κB pathway, are also involved in the regulation of β-catenin-dependent transcriptional activity 47 – 49 . Some studies support that calpain activity is required for wound healing, transgenic mice with overexpressed CAST, which displayed a striking delay in skin wound healing through impaired angiogenesis 13 , 50 . These differences imply that calpain-1/2 modulates angiogenesis via multiple mechanisms, depending on the environment and tissues.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Zheng

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Wound healing is a multistep phenomenon that relies on complex interactions between various cell types. Calpains are a well-known family of calcium-dependent cysteine proteases that regulate several processes, including cellular adhesion, proliferation, and migration, as well as inflammation and angiogenesis. CAPNS1, the common regulatory subunit of Calpain-1 and 2, is indispensable for catalytic subunit stabilization and activity. Calpain inhibition has been shown to reduce organ damage in various disease models. Here, we report that endothelial calpain-1/2 is crucially involved in skin wound healing. Using a mouse genetic model where Capns1 is deleted only in endothelial cells, we showed that calpain-1/2 disruption is associated with reduced injury-activated inflammation, reduced CD31 + blood vessel density, and delayed wound healing. Moreover, in cultured HUVECs, inhibition of calpain reduced TNF-αinduced proliferation, migration, and tube formation. Deletion of Capns1 was associated with elevated levels of IκB and downregulation of β-catenin expression in endothelial cells. These observations delineate a novel mechanistic role for calpain in the crosstalk between inflammation and angiogenesis during skin repair.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Zheng

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…Mutations in the genes of each of the MCR subtypes have been identified in humans and other mammals, as summarized by Switonski et al [ 18 ]. MC1R is prominent in the synthesis of melanin in melanocytes, and mutations are associated with various skin phenotypes and diseases, including increased cancer risk, especially for melanomas [ 19 , 20 , 21 ]. Of interest, three reports indicate an association between disability in MS and MC1R gene single nucleotide polymorphisms leading to MC1R hyporesponsiveness [ 22 , 23 , 24 ].…”

Section: Melanocortin Receptorsmentioning

confidence: 99%

“…A mutation in the MC2R gene with increased expression and stronger response to ACTH has been associated with increased responsiveness to ACTH treatment of infantile spasms [ 25 , 26 ]. MC3R, like MC4R, is involved in energy homeostasis; while several human mutations have been identified [ 20 ], there is a less clear association with obesity for these mutations than for MC4R mutations. MC4R has been extensively investigated in obesity research, and decreased activity of MC4R is the leading monogenic cause of severe early onset obesity [ 27 , 28 ].…”

Section: Melanocortin Receptorsmentioning

confidence: 99%

Melanocortins, Melanocortin Receptors and Multiple Sclerosis

Lisak

Benjamins

2017

Brain Sciences

View full text Add to dashboard Cite

The melanocortins and their receptors have been extensively investigated for their roles in the hypothalamo-pituitary-adrenal axis, but to a lesser extent in immune cells and in the nervous system outside the hypothalamic axis. This review discusses corticosteroid dependent and independent effects of melanocortins on the peripheral immune system, central nervous system (CNS) effects mediated through neuronal regulation of immune system function, and direct effects on endogenous cells in the CNS. We have focused on the expression and function of melanocortin receptors in oligodendroglia (OL), the myelin producing cells of the CNS, with the goal of identifying new therapeutic approaches to decrease CNS damage in multiple sclerosis as well as to promote repair. It is clear that melanocortin signaling through their receptors in the CNS has potential for neuroprotection and repair in diseases like MS. Effects of melanocortins on the immune system by direct effects on the circulating cells (lymphocytes and monocytes) and by signaling through CNS cells in regions lacking a mature blood brain barrier are clear. However, additional studies are needed to develop highly effective MCR targeted therapies that directly affect endogenous cells of the CNS, particularly OL, their progenitors and neurons.

show abstract

“…However, mice lacking both MC3R and MC4R become significantly heavier than Mc4r−/− mice [ 42 ], indicating that they serve non-redundant roles in regulating energy homeostasis. No human MC3R mutations to date have been conclusively linked to severe obesity, even if multiple smaller studies have reported possible associations of MC3R variations with increased body weight [ 90 , 91 , 92 , 93 ], although nowhere near the effect size of that seen with mutations in MC4R. Taking into account all of the available evidence, MC3R is less likely to be related to food intake and more likely to revolve around nutrient partitioning.…”

Section: Genetics Of the Melanocortin Systemmentioning

confidence: 99%

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy

Yeo

Chao

Siegert

et al. 2021

Molecular Metabolism

136

100

View full text Add to dashboard Cite

Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. Scope of review Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. Major conclusions Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.

show abstract

Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity

Cited by 32 publications

References 86 publications

Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Melanocortins, Melanocortin Receptors and Multiple Sclerosis

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy

Contact Info

Product

Resources

About