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Mol Endocrinol. 2014 Mar;28(3):344-56. doi: 10.1210/me.2013-1254. Epub 2014 Jan 30.

RIP140 represses the "brown-in-white" adipocyte program including a futile cycle of triacylglycerol breakdown and synthesis.

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Department of Stem Cell and Regenerative Biology (E.K.), Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138; Institute of Reproductive and Developmental Biology (L.C., E.C., M.G.P.), Faculty of Medicine, Imperial College London, W12 0NN, United Kingdom; Department of Mathematics (M.K., G.M.), Statistics Section, Imperial College London, London SW7 2AZ, United Kingdom; Department of Experimental and Clinical Medicine (A.F., S.C.), University of Ancona, (Politecnica delle Marche), 60126 Ancona, Italy; Division of Metabolic and Vascular Health (M.C.), Warwick Medical School, University of Warwick, Coventry, CV4 7AL, United Kingdom.


Receptor-interacting protein 140 (RIP140) is a corepressor of nuclear receptors that is highly expressed in adipose tissues. We investigated the role of RIP140 in conditionally immortal preadipocyte cell lines prepared from white or brown fat depots. In white adipocytes, a large set of brown fat-associated genes was up-regulated in the absence of RIP140. In contrast, a relatively minor role can be ascribed to RIP140 in the control of basal gene expression in differentiated brown adipocytes because significant changes were observed only in Ptgds and Fabp3. The minor role of RIP140 in brown adipocytes correlates with the similar histology and uncoupling protein 1 and CIDEA staining in knockout compared with wild-type brown adipose tissue (BAT). In contrast, RIP140 knockout sc white adipose tissue (WAT) shows increased numbers of multilocular adipocytes with elevated staining for uncoupling protein 1 and CIDEA. Furthermore in a white adipocyte cell line, the markers of BRITE adipocytes, Tbx1, CD137, Tmem26, Cited1, and Epsti1 were repressed in the presence of RIP140 as was Prdm16. Microarray analysis of wild-type and RIP140-knockout white fat revealed elevated expression of genes associated with cold-induced expression or high expression in BAT. A set of genes associated with a futile cycle of triacylglycerol breakdown and resynthesis and functional assays revealed that glycerol kinase and glycerol-3-phosphate dehydrogenase activity as well as [(3)H]glycerol incorporation were elevated in the absence of RIP140. Thus, RIP140 blocks the BRITE program in WAT, preventing the expression of brown fat genes and inhibiting a triacylglycerol futile cycle, with important implications for energy homeostasis.

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