Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus

Liu, Ting; Ji, Renlei; Tao, Ya‐Xiong

doi:10.1016/j.pharmthera.2021.108044

Cited by 15 publications

(13 citation statements)

References 408 publications

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“…These results indicate distinct non-redundant mechanisms between MC3R and MC4R in regulating energy homeostasis. Furthermore, variants in MC3R and MC4R have been shown to be closely associated with monogenic human obesity [ 14 , 15 , 16 , 17 , 18 ]. In addition, MC4R is also involved in sexual function and reproduction [ 16 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, variants in MC3R and MC4R have been shown to be closely associated with monogenic human obesity [ 14 , 15 , 16 , 17 , 18 ]. In addition, MC4R is also involved in sexual function and reproduction [ 16 , 18 ]. MC3R is also expressed in the periphery and may have other potential physiological functions in regulating cardiovascular function [ 19 , 20 ], immune response [ 21 , 22 , 23 , 24 , 25 ], natriuresis [ 26 ], and timing of sexual maturation [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Tao

2022

Biomolecules

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The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new human (h) MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human MRAP2s are different in C-termini. We investigated the effects of five isoforms of MRAPs, hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c, on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a and hMRAP2c increased and hMRAP1b decreased the cell surface expression. hMRAP1a increased affinity to ACTH. Four MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, and hMRAP2c) decreased the maximal responses in response to α-MSH and ACTH. For hMC4R, hMRAP1a, hMRAP2a, and hMRAP2c increased the cell surface expression of hMC4R. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R trafficking, binding, and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Tao

2022

Biomolecules

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“…MC3R, but not MC4R, was reported to highly express in dopaminergic neurons of the ventral tegmental area (VTA) and regulate the mesolimbic dopaminergic system and reward in a sex-dimorphism manner (23). MC4R widely expressed in the central nervous system (CNS), and its mutations could lead to monogenic obesity in human (24)(25)(26). The last MCR family member to be identified was MC5R in 1994 (27).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

et al. 2022

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The Melanocortin-3 receptor (MC3R) and Melanocortin-4 receptor (MC4R), two members of the key hypothalamic neuropeptide signaling, function as complex mediators to control the central appetitive and energy homeostasis. The melanocortin 2 receptor accessory protein 2 (MRAP2) is well-known for its modulation on the trafficking and signaling of MC3R and MC4R in mammals. In this study, we cloned and elucidated the pharmacological profiles of MRAP2 on the regulation of central melanocortin signaling in a relatively primitive poikilotherm amphibian species, the Mexican axolotl (Ambystoma mexicanum). Our results showed the higher conservation of axolotl mc3r and mc4r across species than mrap2, especially the transmembrane regions in these proteins. Phylogenetic analysis indicated that the axolotl MC3R/MC4R clustered closer to their counterparts in the clawed frog, whereas MRAP2 fell in between the reptile and amphibian clade. We also identified a clear co-expression of mc3r, mc4r, and mrap2 along with pomc and agrp in the axolotl brain tissue. In the presence of MRAP2, the pharmacological stimulation of MC3R by α-MSH or ACTH significantly decreased. MRAP2 significantly decreased the cell surface expression of MC4R in a dose dependent manner. The co-localization and formation of the functional complex of axolotl MC3R/MC4R and MRAP2 on the plasma membrane were further confirmed in vitro. Dramatic changes of the expression levels of mc3r, mrap2, pomc, and agrp in the fasting axolotl hypothalamus indicated their critical roles in the metabolic regulation of feeding behavior and energy homeostasis in the poikilotherm aquatic amphibian.

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“…Of these, the former is characterized by the progressive destruction of pancreatic β cells, while the latter is characterized by peripheral insulin resistance. Although the pathogenesis of DM has been extensively studied, − its treatment still focuses on glycemic control. Therefore, it is of great significance to develop new treatment strategies to solve this major public health problem.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes

Jiang

Sun

Zhou

2022

J. Agric. Food Chem.

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Diabetes mellitus (DM) is a serious metabolic disease characterized by persistent hyperglycemia, with a continuously increasing morbidity and mortality. Although traditional treatments including insulin and oral hypoglycemic drugs maintain blood glucose levels within the normal range to a certain extent, there is an urgent need to develop new drugs that can effectively improve glucose metabolism and diabetes-related complications. Notably, accumulated evidence implicates that the gut microbiota is unbalanced in DM individuals and is involved in the physiological and pathological processes of this metabolic disease. In this review, we introduce the molecular mechanisms by which the gut microbiota contributes to the development of DM. Furthermore, we summarize the preclinical studies of bioactive natural products that exert antidiabetic effects by modulating the gut microbiota, aiming to expand the novel therapeutic strategies for DM prevention and management.

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Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus

Cited by 15 publications

References 408 publications

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Pharmacological Evaluation of Melanocortin 2 Receptor Accessory Protein 2 on Axolotl Neural Melanocortin Signaling

Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes

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