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Abstract

Obesity as a cause of diseases like metabolic syndrome, type 2 diabetes and cardiovascular disease is increasingly becoming a worldwide health problem. Dysfunctional lipid metabolism is a key catalyst for the development of obesity, as impaired triglyceride storage and mobilization (lipolysis) lead to lipotoxicity and cellular stress in white adipose tissue (WAT) and other metabolically active organs. WAT is central to systemic energy metabolism as it has the potential to adapt to external and internal signals by tightly regulated lipid uptake and removal as well as adipocytokine release. Although it is widely accepted that lipolysis in adipose tissue critically determines lipid turnover and obesity, the molecular mechanisms of WAT lipid handling are largely unknown. In this context, the transcriptional co-factors transducin beta like (TBL) 1 and TBL related (TBLR) 1, that have previously been described as regulators of lipid handling in liver, were investigated to establish co-factor function in adipose tissue triglyceride metabolism. Genetic inactivation of TBLR1, but not TBL1, in adipocytes increases triglyceride content of these cells by inhibiting lipolysis at the level of gene transcription. Gene expression profiling revealed an involvement of adipocyte TBLR1 in peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling and fatty acid metabolism pathways. Indeed, TBLR1 interacts with PPARγ and RXR, and treatment with the PPARγ agonist rosiglitazone partly reverses the effects of TBLR1 knockdown on triglyceride hydrolysis. Consistent with its role as a transcriptional co-factor TBLR1 regulates gene expression of the key lipases involved in lipolysis, hormone sensitive lipase (HSL) and adipocyte triglyceride lipase (ATGL). Apart from that, TBLR1 also influences hormone-stimulated activation of lipid breakdown by interfering with the activating adrenoceptor-cAMP-PKA axis at the level of receptor expression. Adipocyte specific deletion of TBLR1 in mice leads to increased body weight and adiposity, adipocyte hypertrophy, as well as impaired lipid mobilization in fasting. Consistent with the finding that impaired lipolysis favors the development of obesity, body weight and adiposity increase in the adipocyte specific TBLR1 knockout (ATKO) mice with proceeding age. When fed a high fat diet, ATKO mice gain more weight and body fat than their wild type littermates, are less glucose tolerant and insulin sensitive and show increased signs of adiposity, namely adipocyte hypertrophy and increased adipocytokine release. Importantly, TBLR1 levels in white adipose tissue increase in states with high lipolytic activity like fasting and obesity in both mice and human patients and correlate with serum parameters and adrenoceptor expression. In summary, TBLR1 expression is activated in situations with augmented lipid mobilization and required for efficient triglyceride breakdown in adipocytes. Thus, manipulating TBLR1 levels in adipocytes may represent a future perspective to treat metabolic diseases like obesity or metabolic syndrome.