Homeobox C4 transcription factor promotes adipose tissue thermogenesis

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-01-24 DOI:10.2337/db24-0675

Ting Yang, Yuxuan Wang, Hang Li, Fengshou Shi, Siqi Xu, Yingting Wu, Jiaqi Xin, Yi Liu, Mengxi Jiang

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引用次数: 0

Abstract

The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.