Chaperone Mediated Autophagy is Necessary for for Brown Adipose Tissue Function
Brown adipose tissue conducts thermogenesis and its activities have been found to be beneficial to the operation of metabolism. Thus a greater proportion of brown adipose tissue versus other types of fat tissue is protective in the context of aging. Unfortunately brown adipose tissue function declines with age, and here researchers provide evidence for this form of fat tissue aging to be caused by a decline in the efficacy of chaperone mediated autophagy, also a feature of aging. This form of autophagy uses chaperone proteins to shuttle damaged or otherwise unwanted molecules into a lysosome for recycling. Like all forms of autophagy the efficiency of its operation is connected to the pace of aging in animal studies; all of the varied processes that help to clear cells of damaged molecules appears beneficial in this context.
Brown adipose tissue (BAT) protects against obesity, diabetes, and cardiovascular disease. During BAT activation, macroautophagy is inhibited, while chaperone-mediated autophagy (CMA) is induced, promoting thermogenic gene expression, adipokine release, oxidative activity, and lipolysis. Aging reduces BAT function and lowers levels of LAMP2A, the rate-limiting CMA component. Pharmacological CMA activation restores BAT activity in aged mice.
To explore the CMA's role in BAT, we generated LAMP2A-deficient brown adipocytes and found that CMA regulates proteins essential for thermogenesis and metabolism. Blocking CMA in BAT reduced energy expenditure, raised blood triglycerides, impaired secretion, and led to an increase of thermogenesis repressors. These findings show that CMA is essential for maintaining BAT function, especially during adaptive thermogenesis. By degrading repressors of thermogenesis, CMA supports BAT activity under cold or metabolic stress.
This work highlights CMA as a key regulator of BAT plasticity and a promising therapeutic target for treating age-related metabolic disorders.