The role of ChREBP-dependent de novo lipogenesis in metabolic and thermogenic activities of brown and white adipose tissue

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The proposed project aims at understanding the functional significance of de novo lipogenesis (DNL) for regulating adaptive thermogenesis as well as cold-induced tissue remodeling. Both processes are triggered in mammals under cold stress and contribute to maintaining body temperature. Adaptive thermogenesis is mediated through ATP-uncoupled fuel oxidation in brown adipocytes (in brown adipose tissue) and beige adipocytes (in white adipose tissue), collectively called "thermogenic adipocytes". As a consequence of chronic cold exposure, more thermogenic adipocytes and vascular endothelial cells are formed, increasing thermogenic capacity. Recent studies show that thermogenic adipocytes are present in adult humans and that the number can be increased by repeated cold stimuli, providing new opportunities for the prevention and treatment of overweight-associated diseases. DNL, the synthesis of fatty acids from non-lipid precursors such as glucose, is strongly induced in activated thermogenic adipocytes. The induction mechanism and the physiological significance are, however, not known. Here, we postulate that the transcription factor carbohydrate response element-binding protein (ChREBP) plays a key role by inducing DNL enzymes in thermogenic adipocytes, and that this is necessary for proper cold adaptation. Our preliminary work using ChREBP-deficient mice shows that DNL in brown adipose tissue is especially dependent on ChREBP. For assessing the functional relevance of DNL, metabolic in vivo and in vitro studies with and without ChREBP deficiency are proposed. Studies analyzing angiogenesis and vascularization, cell organell adaptations, systemic lipid and fuel metabolism as well as adaptive thermogenesis are planned to understand the functional role of DNL in thermogenic adipocytes.