Dataset Information

Characterization of the chicken melanocortin 5 receptor and its potential role in regulating hepatic glucolipid metabolism.

ABSTRACT: Melanocortin receptors (MC1R-MC5R) and their accessory proteins (MRAPs) are involved in a variety of physiological processes, including pigmentation, lipolysis, adrenal steroidogenesis, and immunology. However, the physiological roles of MC5R are rarely characterized in vertebrates, particularly in birds. In this work, we cloned the full-length cDNA of chicken MC5R and identified its core promoter region. Functional studies revealed that cMC5R was more sensitive to ACTH/α-MSH than β-MSH/γ-MSH, and was coupled to the cAMP/PKA signaling pathway. We demonstrated that MRAP2 decreased MC5R sensitivity to α-MSH, whereas MRAP1 did not have a similar effect, and that both MRAPs significantly reduced MC5R expression on the cell membrane surface. Transcriptome and qPCR data showed that both MRAP1 and MC5R were highly expressed in chicken liver. Additionally, we observed that ACTH might increase hepatic glucose production and decrease lipogenesis in primary hepatocytes, and dose-dependently downregulated the expression levels of ELOVL6 and THRSPA genes. These findings indicated that ACTH may act directly on hepatocytes to regulate glucolipid metabolism, which will help to understand the function of MC5R in avian.

SUBMITTER: Zhang X

PROVIDER: S-EPMC9583845 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Characterization of the chicken melanocortin 5 receptor and its potential role in regulating hepatic glucolipid metabolism.

Zhang Xiao X Su Jiancheng J Huang Tianjiao T Wang Xinglong X Wu Chenlei C Li Jing J Li Juan J Zhang Jiannan J Wang Yajun Y

Frontiers in physiology 20221006

Melanocortin receptors (MC1R-MC5R) and their accessory proteins (MRAPs) are involved in a variety of physiological processes, including pigmentation, lipolysis, adrenal steroidogenesis, and immunology. However, the physiological roles of MC5R are rarely characterized in vertebrates, particularly in birds. In this work, we cloned the full-length cDNA of chicken MC5R and identified its core promoter region. Functional studies revealed that cMC5R was more sensitive to ACTH/α-MSH than β-MSH/γ-MSH, a ...[more]

PMID: 36277187

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Project description:The management of hyperglycemia and lipid metabolism is pivotal for the treatment of type 2 diabetes mellitus (T2DM). Metformin hydrochloride (DMBG) remains the most widely prescribed medication for this condition. This study aimed to elucidate the effects and underlying mechanisms by which DMBG enhances glucolipid metabolism using both in vivo and in vitro experimental models. Animal models were established using high-fat diet (HFD)-fed mice, while cellular models utilized palmitic acid (PA)-induced HepG2 cells. In vivo, the impact of DMBG on glucolipid metabolism was evaluated through measurements of insulin and HbA1c levels, intraperitoneal glucose tolerance tests (ipGTT), intraperitoneal insulin tolerance tests (ipITT), as well as histological assessments with hematoxylin-eosin (HE) and Oil-red O staining. Mitochondrial function was assessed via biochemical assays of TBARS, SOD, ATP, and H2O2 levels in liver tissue, alongside determinations of mitochondrial membrane potential, ROS production, mtDNA content, and SIRT5 mRNA expression. For in vitro analysis, glucose consumption, mitochondrial membrane potential, ROS levels, and protein expressions of AMPK and PGC-1α were quantified in HepG2 cells. Western blotting and co-immunoprecipitation (co-IP) techniques were employed to investigate the mechanistic pathways involved. Treatment with DMBG resulted in reduced levels of free fatty acids, body weight, and fat mass, while also alleviating hyperglycemia and hepatic lipid accumulation in HFD-fed mice. Furthermore, DMBG restored impaired mitochondrial function in these animals and increased SIRT5 expression via AMPK activation. In vitro, DMBG mitigated PA-induced alterations in glucose consumption and mitochondrial dysfunction in HepG2 cells, an effect that was abrogated upon SIRT5 knockdown. Overexpression of SIRT5 led to enhanced trifunctional enzyme subunit-alpha (ECHA) desuccinylation at the K540 site, thereby increasing its activity. Collectively, our findings indicate that DMBG improves hepatic glucolipid metabolism through a mechanism involving SIRT5-mediated ECHA desuccinylation, potentially offering a new therapeutic avenue for T2DM.

Dataset Information

Characterization of the chicken melanocortin 5 receptor and its potential role in regulating hepatic glucolipid metabolism.

Publications

Characterization of the chicken melanocortin 5 receptor and its potential role in regulating hepatic glucolipid metabolism.

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