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Abstract

Adipose tissue exists in three shades: White adipose tissue (WAT), the site of energy storage, brown adipose tissue (BAT), which burns nutrients to generate heat and maintain body temperature, and brown in white adipose tissue (brite AT), which represents WAT adapting BAT features in cold exposure. Thermogenically active BAT has been discovered in adult humans and inversely correlates with obesity and insulin resistance. The link between impaired insulin sensitivity and the browning of adipose tissue has not been clear however. While the necessity for insulin for normal development of adipose tissues is well recognised, the dependence of the recruitment of brite adipocytes in functional insulin signalling has not been investigated before. We show that β3-adrenergic stimulation can overcome insulin deficiency and fully activate the brown program in WAT. Vice versa, while it is known that the presence of brite AT allows enhanced glucose clearance, it has not previously been investigated whether this tissue is more insulin sensitive than white. Surprisingly we found that brite cells and tissues demonstrated markedly elevated glucose uptake even in the absence of insulin, and while insulin augmented glucose uptake to both white and brite AT, the degree of this response did not differ between the two types of adipose tissue. In line with these findings, we observed a marked induction of the insulin independent glucose transporter solute carrier family 2 (GLUT-1) upon browning of WAT. Thus we demonstrate for the first time that insulin signalling is dispensable for brite recruitment and not improved in browned cells or tissues. The nuclear receptor co-regulator Transducin (beta)-like 1 X-linked receptor 1 (TBLR) is a known transcriptional master-regulator that carries out distinct metabolic roles in liver and WAT. We show that, being part of the machinery of a general regulatory mechanism, the actions of TBLR depend largely on its environment, since TBLR deficiency in BAT lead to a distinct phenotype compared to other tissues and its role in mature cells differs from its role during adipogenic differentiation. During differentiation, TBLR balanced growth versus differentiation cues and its depletion reduced glucose import and metabolic activity of mature adipocytes. In thermogenically active mature brown adipocytes or BAT, Tblr expression was found to be cold-inducible downstream of the MAPK pathway. BAT-specific knock out of TBLR could be largely compensated for, since gene expression, adiposity, lipid or glucose handling and respiration in these mice (BATKO mice) were normal. However, BATKO mice had impaired maximal thermogenic capacity upon acute β3-adrenergic stimulation. Surprisingly, BAT-specific TBLR KO had systemic effects on gene expression and lead to reduced serum very low density lipoprotein (VLDL) both in the cold and at thermoneutrality. After excluding altered hepatic production or loss to feces, we observed elevated lipid deposition to WAT. Based on our findings, we hypothesise that BATKO mice differentially secrete factors that affect peripheral metabolism. Understanding the recruitment and regulation of different shades of adipose tissue is a crucial step towards pharmaceutically targeting a disadvantageous metabolic state. This thesis offers new insights on the dependence of whole body metabolism on the function of thermogenically active adipose tissue.