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Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance

Abstract

Obesity develops as a result of altered energy homeostasis favoring fat storage. Here we describe a new transcription co-regulator for adiposity and energy metabolism, SERTA domain containing 2 (TRIP-Br2, also called SERTAD2). TRIP-Br2–null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of these knockout mice showed greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The knockout mice also have higher energy expenditure because of increased adipocyte thermogenesis and oxidative metabolism caused by upregulating key enzymes in their respective processes. Our data show that a cell-cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data, together with the observation that TRIP-Br2 expression is selectively elevated in visceral fat in obese humans, suggests that this transcriptional co-regulator is a new therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.

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Figure 1: Regulation of TRIP-Br2 in obesity and the effects of TRIP-Br2 ablation on obesity.
Figure 2: Effects of TRIP-Br2 ablation on glucose homeostasis and physiological parameters.
Figure 3: TRIP-Br2 ablation enhances lipolysis by upregulation of HSL and Adrb3 expression.
Figure 4: TRIP-Br2 ablation promotes energy expenditure and fatty acid oxidation.
Figure 5: TRIP-Br2–Flag represses HSL and Adrb3 gene expression by recruitment to E2F consensus binding sites.

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Acknowledgements

The authors thank C.R. Kahn (Joslin Diabetes Center) for providing reagents and discussions, E. Rosen for discussions, E. Morgan and K. Parlee for excellent assistance in the preparation of this manuscript, H. Li for assistance with hormone assays, O.P. McGuinness for mouse metabolic phenotyping, L. Fajas (INSERM) for providing reagents, M. Mori (Joslin Diabetes Center) for providing samples and R. Zechner for providing the protocol for triglyceride hydrolase activities. Funds to generate some reagents used in this research were supported by US National Institutes of Health (NIH) grant RO1 DK 67536 (R.N.K.) and the Joslin Graetz Bridge Funds (R.N.K.), NIH grants R01 HL073168 (A.D.), K99 DK090210 (C.W.L.), DK51586 and DK58825 (S.R.F.) and the Joslin Diabetes and Endocrinology Research Center Specialized Assay and Advanced Microscopy Cores (NIH P30 DK36836). The human studies were supported by a grant of the Deutsche Forschungsgemeinschaft Clinical Research group 'Atherobesity' (KFO152; BL 833/1-1). C.W.L. was supported by a US National Institutes of Health Interdisciplinary training grant (1RL9EB008539-01) (SysCODE), K99 DK090210 and R00 DK090210. D.K. is the recipient of a research fellowship (Manpei Suzuki Diabetes Foundation, Japan) and a Juvenile Diabetes Research Foundation postdoctoral Fellowship. S.I.-H.H. and J.K.C. were supported by the R. Glenn Davis (Dialysis Center, Inc.) Endowed Professorship in Clinical and Translational Medicine and by the University of Florida, Division of Nephrology Gatorade Fund. S.I.-H.H. was supported as a Scholar of the Clinical Translational Science Institute at the University of Florida.

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C.W.L., J.K.C., S.I.-H.H. and R.N.K. conceived the project. C.W.L. and R.N.K. designed the experiments. A.D. analyzed human data. C.W.L., J.B., J.K.C., C.V., D.K., J.H., C.M., M.K.H., K.T. and H.-J.K. performed experiments and analyzed data. M.B. contributed human samples and supervised human expression analysis. S.R.F. supervised experiments. D.L., S.I.-H.H., Y.-H.T. and L.G. contributed reagents. C.W.L. and R.N.K. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Stephen I-Hong Hsu or Rohit N Kulkarni.

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Liew, C., Boucher, J., Cheong, J. et al. Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance. Nat Med 19, 217–226 (2013). https://doi.org/10.1038/nm.3056

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