New molecular auto-control system to avoid an excessive brown adipose tissue activity

May 07, 2020

Scientific team found a new metabolism regulation system for the brown adipose tissue using the kallikrein-kinin hormonal system, so far related to the physiology of the renal and cardiovascular system and inflammation and pain processes. This molecular auto-control system of lipidic metabolism, so far unknown, could help prevent the damaging effects derived from an excessive activation of the brown adipose tissue.

The new study, published in the journal Nature Communications, is led by Professor Francesc Villarroya, from the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB), and member of the Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBERobn) from the Health Institute Carlos III. Other participants in the study are the experts from the University of Santiago de Compostela, Maastricht University (the Netherlands), and Humboldt University, the Center for Cardiovascular Research and Berlin Institute of Health (Germany).

Brown adipose tissue: how to auto-control its activity

The brown adipose tissue's main function is to burn calories and create body heat using fat (thermogenesis). It also acts as an endocrine organ able to secrete factors that activate fat and carb metabolism and help prevent pathologies such as obesity and diabetes. However, an excessive and uncontrolled activity of the tissue could cause damaging effects such as cachexia -excessive loss of body weight- present in some types of cancer.

The new paper describes for the first time the relation of the kallikrein-kikin System with metabolic regulation systems in the brown adipose tissue. This tissue is activated as a reaction to environmental stimuli -temperature, diet, etc.- and its response is channelled through the sympathetic nervous system and hormonal factors. It was believed that the interruption of these inductors was the authentic limiting the thermogenic activity of fat.

"We now know that some active mechanisms can restrain this and that the own positive inductors can activate the Kallikrein-kinin system which acts as an auto-control mechanism to remove the brown adipose tissue activity", notes Professor Villarroya, head of the research group on Genetics and Molecular Biology of Mitochondrial Proteins and Associated Pathologies of the UB.

"Although it may look contradictory -the activator signals determine the self-control of the system- and this could be explained if we consider the importance of the fine regulation of thermogenesis to avoid too much metabolites to burn without any physiological aim for the body", notes the expert.

Thermogenesis: beyond providing cells with energy

The biochemical mechanism to burn calories and make body heat with fat -known mitochondrial uncoupling- is a process that alters the bioenergetics of the mitochondria, the cell organelle that obtains energy. In this specific mechanism, the activity of the mitochondria is not the common one -oxidising substrates to get ATP molecules to provide energy to cells- but it derives in the dissipation of metabolic energy in form of heat.

An excessive activity of the brown adipose tissue creates pathological picture associated to an uncontrolled energetic waste and fast weight loss (cachexia, etc.) in patients with tumours. There are many enigmas about a process, that despite being within the clinical field, hardens the recovery of the affected patients by burning when the energy waste and activity of the brown adipose tissue skyrockets.

Before knowing about the physiology of the brown adipose tissue, the mitochondrial uncoupling was the altered mechanism for the intoxication in workers in army factories during the World War I. Due to the exposure to dinitrophenol compound -toxic that generates mitochondrial uncoupling uncontrolledly in all body tissues- the temperature of the intoxicated workers increased and the weight loss was severe in the affected ones. During the 20th century's seventies, the scientific community could identify that mitochondrial uncoupling was a process that occurs in a controlled way in the mitochondria of the brown adipose tissue through the UCP1 protein.

"It is clear that such a mechanism should be highly controlled in order to prevent problems caused by an uncontrolled activity. Actually, it is possible for the evolution to have confined this mechanism within the mitochondria in a specialized cell -brown adipocyte- and not all body tissues as a security mechanism", says Villarroya.

The new study could shed light on strategies to moderate the thermogenic activity in pathological situations (cancer, etc.). In this context, the discovery of the local action of of the auto-control system of kallikrein-kinkin on the brown adipose tissue sheds lights on future pharmacological tools for the fight and control of metabolic diseases.

University of Barcelona

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