p53 Regulates a miRNA-Fructose Transporter Axis in Brown Adipose Tissue Under Fasting

Frontiers in Genetics

Renate Schreiber¹  Michael Schupp²  Georgia Lenihan-Geels³  Tim J. Schulz³  Michael Karbiener⁴  Elisabeth Moyschewitz⁵  Isabel Reinisch⁵  Andreas Prokesch⁵  Helene Michenthaler⁵  Magnus Domingo⁵  Ingeborg Klymiuk⁵  Markus Galhuber⁵  Jelena Krstic⁵  Dagmar Kratky⁶  Nemanja Vujić⁶  Roland Malli⁶  Tobias Madl⁶  Fangrong Zhang⁸ 

[1] BioHealth Graz, Graz, Austria;Cardiovascular Metabolic Renal (CMR)- Research Center, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, Berlin, Germany;Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany;Global Pathogen Safety, Takeda Austria Manufacturing AG, Austria;Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria;Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria;Institute of Molecular Biosciences, University of Graz, NAWI Graz, Graz, Austria;Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China;

关键词: p53;    metabolism;    fasting;    brown adipose tissue;    miRNA;    fructose;   

DOI  :  10.3389/fgene.2022.913030

来源: DOAJ

【 摘 要 】

Active thermogenic adipocytes avidly consume energy substrates like fatty acids and glucose to maintain body temperature upon cold exposure. Despite strong evidence for the involvement of brown adipose tissue (BAT) in controlling systemic energy homeostasis upon nutrient excess, it is unclear how the activity of brown adipocytes is regulated in times of nutrient scarcity. Therefore, this study aimed to scrutinize factors that modulate BAT activity to balance thermogenic and energetic needs upon simultaneous fasting and cold stress. For an unbiased view, we performed transcriptomic and miRNA sequencing analyses of BAT from acutely fasted (24 h) mice under mild cold exposure. Combining these data with in-depth bioinformatic analyses and in vitro gain-of-function experiments, we define a previously undescribed axis of p53 inducing miR-92a-1-5p transcription that is highly upregulated by fasting in thermogenic adipocytes. p53, a fasting-responsive transcription factor, was previously shown to control genes involved in the thermogenic program and miR-92a-1-5p was found to negatively correlate with human BAT activity. Here, we identify fructose transporter Slc2a5 as one direct downstream target of this axis and show that fructose can be taken up by and metabolized in brown adipocytes. In sum, this study delineates a fasting-induced pathway involving p53 that transactivates miR-92a-1-5p, which in turn decreases Slc2a5 expression, and suggests fructose as an energy substrate in thermogenic adipocytes.

【 授权许可】

Unknown