TBLR1 in Brown Adipose Tissue Function

Obesity and associated metabolic disorders such as insulin resistance and type 2 diabetes mellitus have become a major health burden within the last decades. A new strategy to counter-act obesity lays in the activation of brown adipose tissue owing to its vast thermogenic capacity und its consequent great ability to burn energy. However, to use the potential of thermogenic adipose tissue, it is essential to understand molecular mechanism that regulate its function. In this project it is aimed to study the role of the transcriptional cofactor TBLR1 (transducin beta-like related 1) for the functionality of thermogenic adipose tissue. Therefore, a genetically modified mouse line was created, in which the Tblr1 gene is deleted specifically in thermogenic fat cells. With this novel mouse line it is planned to perform a comprehensive metabolic and molecular biological characterisation to define the role of TBLR1 for brown fat function and to decipher its influence on systemic energy homeostasis. In addition, the analysis aims to identify TBLR1 dependent transcriptional networks that regulate metabolic pathways in brown fat cells. The results of this study will improve the understanding of brown fat physiology and clarify fundamental mechanisms how brown adipose tissue is transcriptionally regulated by TBLR1.

An increasing number of people with obesity and associated metabolic disorders, such as type 2 diabetes, has become a pressing healthcare challenge in many nations. In principle, obesity develops in situations where there is an imbalance between energy intake and energy expenditure. This development is usually favoured by a life style that is characterised by reduced physical activity and/or by increased consumption of high caloric foods. While the main function of white adipose tissue is to store energy in form of lipids, brown adipose tissue holds a remarkable capacity for substrate oxidation, which can be activated by cold exposure. Responsible for this feature is the presence of uncoupling protein 1 (UCP1) in brown adipocytes, which drives the dissipation of energy as heat and thereby burns calories. The activation of brown adipose tissue has therefore become an attractive approach to counteract obesity and related metabolic comorbidities. A prerequisite for using this potential, however, lies in understanding of the molecular mechanisms that regulate thermogenesis. In this project, we aimed to elucidate the role of the protein transducin beta-like related 1 (TBLR1) for the functionality of brown adipose tissue. TBLR1 is a transcriptional cofactor and is therefore involved in regulating gene expression. It was previously shown to be involved in regulating lipid metabolism related genes in the liver and white adipose tissue, while its function in brown adipose tissue was yet to be determined. To study the function of TBLR1 in brown fat, we generated a genetically modified mouse line in which the gene encoding TBLR1 as well as the gene encoding the functionally related protein transducin beta-like 1 (TBL1) were deleted specifically in thermogenic fat cells. We performed a comprehensive metabolic analysis of these mice and evaluated how the deficiency of TBLR1/TBL1 in brown adipose tissue affected systemic energy expenditure upon cold exposure. In addition, we performed high-throughput sequencing of wildtype - and TBLR1/TBL1 deficient brown adipose tissues. Thereby, we identified a novel role for TBLR1/TBL1 in regulating specific genes linked to brown adipose tissue metabolism and the adaptive response to cold. The results of this study improved the understanding of the physiology of brown fat and clarified how TBLR1/TBL1 transcriptionally modulate gene programs that control the activation of brown adipose tissue. The novel insights generated in this study can also serve as basis for future studies addressing the therapeutic potential of modulating TBLR1/TBL1 in brown fat in obesity-associated diseases.