Researchers decipher mechanism preventing the loss of brown adipose tissue activity during ageing

A study led by the University of Barcelona has identified a key molecular mechanism in the loss of brown fat activity during ageing. The study opens up new perspectives for designing strategies to boost the activity of this tissue and prevent chronic metabolic and cardiovascular diseases as the population ages.

From left to right, Tania Quesada-López, Francesc Villarroya, Albert Blasco-Roset, Marta Giralt, Alberto Mestres-Arenas, Joan Villarroya, Aleix Gavaldà-Navarro and Rubén Cereijo (Credit: University of Barcelona).

In the animal study led by Professor Joan Villarroya, from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), based at the Barcelona Science Park-UB, and the CIBER Area for Physiopathology of Obesity and Nutrition (CIBEROBN), the researchers found that the thermogenic activation of brown fat is associated with an increase in a cellular process known as chaperone-mediated autophagy (CMA), which enhances the selective degradation of specific proteins.

Brown adipose tissue is the main organ capable of producing body heat from fat (thermogenesis). It has a protective function against obesity, type 2 diabetes and cardiovascular disease, and is activated in response to certain factors - such as cold or dietary stimuli - in which the body reacts by increasing the metabolism of excess calories consumed. However, the molecular mechanisms that cause its activity to decrease during ageing are still unknown.

As the body ages, brown adipose tissue activity decreases, fewer calories are burned, and this can contribute to obesity and certain chronic cardiovascular diseases that worsen with age. During ageing, chaperone-mediated autophagy decreases, causing a loss of brown adipose tissue activity.

“Therefore, acting on chaperone-mediated autophagy may play a key role in modulating the tissue activity”, explained Professor Villarroya. “The function of chaperone-mediated autophagy decreases is the selective elimination of proteins. What we have observed is that this process is responsible for the degradation of these repressor proteins, enabling brown fat activity.”

The activity of brown adipose tissue is tightly regulated to prevent uncontrolled metabolization of different chemical substrates. This control is ensured by proteins that act as repressors of thermogenic activity and are activated whenever the body does not need to activate brown adipose tissue.

For many years, attempts have been made to design drugs capable of activating brown adipose tissue to prevent its decline, but until now, the various options have generated unwanted side effects.

“Effective experimental drugs are now beginning to emerge to modulate chaperone-mediated autophagy. In the study, ageing mice were treated with these drugs, and the adipose tissue was able to maintain its activity and improve metabolic function despite ageing,” she added.

For now, some preclinical drugs designed to activate this process are available, originally developed for the potential treatment of neurodegenerative diseases, in which proteins with pathological action often accumulate.

On the clinical side, the use of these compounds could be considered to prevent the inactivation of brown fat with ageing or in other conditions where low brown adipose tissue activity has pathological consequences, such as obesity or diabetes.

For this reason, the research team is studying how chaperone-mediated autophagy could be used to boost metabolic energy expenditure and thus control obesity and its negative cardiometabolic effects.

“We are pursuing these lines of research both in experimental models and in initial studies in patients, in collaboration with several hospitals,” concluded Villarroya.

​​​​The findings were reported in the paper, 'Chaperone-mediated autophagy controls brown adipose tissue thermogenic activity', published in Science Advances. To access this paper, please click here