Chaperone-mediated autophagy controls brown adipose tissue 2 thermogenic activity

ABSTRACT: The activity of brown fat, a tissue mediating non-shivering thermogenesis, is associated with protection against obesity, diabetes, and cardiovascular disease. In response to thermogenic stimuli, brown adipose tissue (BAT) increases its activity through extensive cellular and tissue plasticity. While macroautophagy is typically inhibited during BAT thermogenic activation, we found that chaperone-mediated autophagy (CMA), a selective type of autophagy, is instead induced. CMA induction enhances both basal and cAMP-stimulated activity of brown adipocytes, as evidenced by increased expression of thermogenesis-related genes, enhanced release of brown adipokines, elevated cellular oxidative activity, and increased lipolysis. In aging, when BAT activity declines, LAMP2A—the limiting CMA component—is downregulated in BAT. However, pharmacological activation of CMA restores BAT activity in aged mice. To investigate the consequences of this CMA failure in BAT, we generated brown adipocytes knock down for LAMP2A and using comparative proteomics identified that CMA regulates levels of proteins involved in BAT thermogenic and metabolic activity. We demonstrate that selective CMA blockade in interscapular BAT in mice leads to reduced energy expenditure, increased triglyceridemia, lower expression of thermogenic markers and BAT-secretory functions, and to accumulation of thermogenesis repressors upon thermogenic activation. Overall, these findings support the essential role of CMA in BAT function and adaptation to thermogenic activation. CMA facilitates the timely degradation of thermogenic repressors, thereby promoting adaptive enhancement of thermogenic activity.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Fat Cell

SUBMITTER: Tania Paloma Quesada-López  

LAB HEAD: Joan Villarroya Terrade

PROVIDER: PXD062807 | Pride | 2025-09-30

REPOSITORIES: Pride