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bioRxiv · 10.1101/2025.03.11.641984

BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity

Philippe, M. A.·Fruchet, B.·Cagninacci, L.·Beaudoin, L.·Gadault, A.·Venteclef, N.·Challet, E.·Lehuen, A.·Rogner, U. C.·Toubal, A.
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Abstract

Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of BMAL2 are associated with obesity and T2D. In this study we report that Bmal2 invalidation in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing Tnf expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications. HighlightsO_LIThe transcription factor BMAL2 is involved in metabolic complications of obesity in a mouse model of diet-induced obesity C_LIO_LIInvalidation of Bmal2 worsens insulin resistance and hepatic steatosis induced by high fat diet C_LIO_LIInvalidation of Bmal2 impairs visceral adipose tissue adaptation capacity in promoting inflammation and adipose progenitor decline C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/641984v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1d60e1eorg.highwire.dtl.DTLVardef@38daaaorg.highwire.dtl.DTLVardef@9c0040org.highwire.dtl.DTLVardef@1d484bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Philippe, M. A., Fruchet, B., Cagninacci, L., Beaudoin, L., Gadault, A., Venteclef, N., Challet, E., Lehuen, A., Rogner, U. C., Toubal, A.. 2025-03-12. BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity. https://doi.org/10.1101/2025.03.11.641984

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