08.07.2020: It sounds like an alternate version of Star Wars in which the dark side wins: brown fat defeats white fat. Specifically, the activation of brown adipose tissue is seen as a promising approach in the fight against obesity. Researchers at the University of Veterinary Medicine Vienna have uncovered some important molecular causes for obesity, which could lead to a therapeutic solution that makes use of the positive properties of brown adipose tissue. In their study, the researchers describe the mechanistic and genetic relationships between STAT5 transcription factors and the metabolic processes in brown adipose tissue and their effect on the metabolism of mammals in general. 

Obesity and associated comorbitites such as type 2 diabetes, as well as the increased risk of cancer in overweight persons, represent a growing medical and economic problem. Especially during the Covid-19 pandemic, obesity and type 2 diabetes have proven to be risk factors contributing to an increased mortality among affected persons. According to the latest WHO data, 54% of adults in Austria are overweight, of which ∼20% are classified as obese (WHO, data for 2016). While genetic and endocrine defects comprise only a small number of the cases, the main causes for comorbidities can be found in consuming too much and moving too little, which results in excess calories. Increasing energy expenditure through activation of thermogenesis (heat production) of brown adipose tissue is an attractive approach to counteract obesity. In order to develop therapies based on this approach, it is important to understand the molecular mechanisms that control the functionality of brown adipose tissue.

Brown adipose tissue increases energy expenditure

Unlike white fat, brown fat can produce heat via thermogenesis. Brown fat cells contain a high density of mitochondria and exhibit an increased expression of uncoupling protein 1 (UCP1), a protein that is found in the mitochondrial membrane of brown adipose tissue. UCP1 can uncouple the mitochondrial respiratory chain from ATP synthesis, thereby releasing stored energy in the form of heat, which leads to an increase in energy expenditure. Brown fat thermogenesis is activated mainly through cold exposure or by treatment with β₃-adrenergic agonists. Chronic β₃-adrenergic stimulation makes it possible to “brown” white adipose tissue – and this is exactly what the researchers from Vetmeduni Vienna investigated in a collaborative study involving several laboratories.

First-ever proof of the thermogenic effect of STAT5

Several members of the JAK-STAT signalling pathway family, composed of Janus kinases (JAK) and signal transducer and activator of transcription (STAT) proteins, have already been linked to the regulation of adipose tissue, but it remains unknown who exactly activates or deactivates what and how. Previous work by research groups at Vetmeduni have demonstrated the importance of the protein STAT5 during the development of fat cells and as a regulator in the lipid metabolism of white fat. It was not yet known, however, whether STAT5 also plays a role in the functionality of thermogenic brown adipose tissue. In the study, published in the scientific journal Molecular Metabolism, Richard Moriggl’s Functional Cancer Genomics laboratory at Vetmeduni Vienna provides the first-ever evidence that STAT5 is essential for the functionality and adrenalin-mediated (β-adrenergic) responsiveness of thermogenic adipose tissue. This shows that STAT5 plays a central role in lipid metabolism. The mitochondrial processes were elucidated in collaboration with the Elena Pohl research group at Vetmeduni.

STAT5 is necessary for temperature maintenance

The researchers found that genetically modified mice lacking STAT5 in their adipose tissue are more sensitive to cold stress and that STAT5 deletion blocked lipid mobilization in brown fat. In addition, primary differentiated brown adipocytes without STAT5 showed reduced mitochondrial respiration. “We found that increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of the thermogenic markers including UCP1, while decreased lipid mobilization was linked to a decreased activity of the β-adrenergic signalling pathway. In addition, the brown remodelling of white adipose tissue was diminished following chronic β₃-adrenergic stimulation in mice lacking STAT5 in their adipose tissue,” say both first authors Doris Kaltenecker and Katrin Spirk from the Institute of Animal Breeding and Genetics.

Inactivation of STAT5 as possible therapy for metabolic diseases

The present study shows for the first time that STAT5 is crucial for the β-adrenergic responsiveness of brown adipose tissue. Not only is STAT5 a key factor for the mobilization of free fatty acids in tissue to fuel thermogenesis and mitochondrial respiration, it also determines the capacity of the β-adrenergic-induced browning of white fat. According to the first authors, “These novel insights into the requirement of STAT5 for the physiology of thermogenic fat and its role in lipid metabolism can pave the way for future studies addressing how the inactivation of STAT5 affects the outcomes in metabolic diseases associated with obesity.” These findings are of particular importance in basic translational research, especially regarding the use of STAT5 inhibitors in cancer research, with infectious diseases or in cases of chronic inflammation. The physiological insights into complex metabolic processes are of fundamental significance with regard to the development of clinically relevant new JAK-STAT5 inhibitors, which are being realised at full speed in the Richard Moriggl lab (https://moriggllab.com/).

The article “STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue” by Doris Kaltenecker, Katrin Spirk, Frank Ruge, Florian Grebien, Marco Herling, Anne Rupprecht, Lukas Kenner, Elena E. Pohl, Kristina M. Mueller and Richard Moriggl was published in Molecular Metabolism.