Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution

• Published in: Cell reports (Cambridge) Vol. 34; no. 2; p. 108624
• Main Authors: Schlein, Christian, Fischer, Alexander W., Sass, Frederike, Worthmann, Anna, Tödter, Klaus, Jaeckstein, Michelle Y., Behrens, Janina, Lynes, Matthew D., Kiebish, Michael A., Narain, Niven R., Bussberg, Val, Darkwah, Abena, Jespersen, Naja Zenius, Nielsen, Søren, Scheele, Camilla, Schweizer, Michaela, Braren, Ingke, Bartelt, Alexander, Tseng, Yu-Hua, Heeren, Joerg, Scheja, Ludger
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2021; Elsevier
• Subjects: Adipose Tissue, Brown - metabolism; Animals; brown adipose tissue; cardiolipins; ChREBP; de novo lipogenesis; energy expenditure; fatty acid synthesis; fatty acids; Fatty Acids - biosynthesis; Humans; lipidome; Mice; mitochondria; mitophagy; non-shivering thermogenesis; phospholipids; thermoneutrality; triacylglycerols; whitening; fatty acids; mitochondria; de novo lipogenesis; phospholipids; energy expenditure; whitening; cardiolipins; ChREBP; mitophagy; non-shivering thermogenesis; brown adipose tissue; fatty acid synthesis; thermoneutrality; triacylglycerols; lipidome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108624

Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans. [Display omitted] •ChREBP controls de novo lipogenesis (DNL) in BAT•DNL-derived lipids are enriched in BAT of mice in response to thermoneutral housing•Thermoneutrality causes loss of mitochondria and UCP1 by mitophagy in BAT•DNL-linked lipid remodeling and BAT involution are prevented by ChREBP deficiency Schlein et al. show that carbohydrate-response element-binding protein (ChREBP) controls de novo lipogenesis (DNL) in brown adipose tissue (BAT) and determines BAT whitening in response to thermoneutral housing. ChREBP deficiency prevents enrichment of DNL-derived lipids and mitophagy during BAT involution, which is associated with higher thermogenic capacity.