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Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat

Abstract

Maintenance of body temperature is essential for the survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation1. Owing to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans2,3,4,5, BAT holds great promise for the treatment of obesity and metabolic syndrome1. Rodent data suggest the existence of two types of brown fat cells: constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the interscapular region of mice; and recruitable BAT (rBAT), which resides within white adipose tissue (WAT)6 and skeletal muscle7, and has alternatively been called beige8, brite9 or inducible BAT10. Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT10,11,12. Here we use mouse models to provide evidence for a systemically active regulatory mechanism that controls whole-body BAT activity for thermoregulation and energy homeostasis. Genetic ablation of the type 1A BMP receptor (Bmpr1a) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown-fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease.

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Figure 1: Loss of Bmpr1a impairs cBAT formation by decreasing embryonic progenitor proliferation.
Figure 2: Ablation of Bmpr1a in brown pre-adipocytes derived from the Myf5 + lineage inhibits differentiation.
Figure 3: Specific ablation of cBAT results in a compensatory response of increased browning by enhanced sympathetic input to WAT.
Figure 4: Loss of sympathetic innervation causes atrophy of cBAT and compensatory browning of white fat.

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Acknowledgements

This work was supported in part by National Institutes of Health (NIH) grants R01 DK077097 (Y.-H.T.), and Joslin Diabetes Center’s Diabetes Research Center (DRC; P30 DK036836 from the NIDDK), a research grant from the Eli Lilly Research Foundation, and by funding from the Harvard Stem Cell Institute (to Y.-H.T.). T.J.S. was supported by the Mary K. Iacocca Foundation and the German Research Foundation (DFG; SCHU2445/1-1). P.H. was supported by a Scientist Development Grant from the American Heart Association (0730285N). K.L.T. was supported by NIH fellowships (T32 DK007260 and F32 DK091996). R.X. was supported by Project 985III-YFX0302 and NSFC81070680 from the National Natural Science Foundation of China. The authors thank Stryker Regenerative Medicine for the gift of recombinant BMP7. We acknowledge V. Kaartinen, B. Kahn, K. Lyons and P. Soriano for providing floxed Acvr1 mice, FABP4-Cre mice, Bmpr1b heterozygous mice and Myf5-Cre mice, respectively. The authors thank C. R. Kahn, L. J. Goodyear, E. Kokkotou and D. Breault for comments on the manuscript. The authors wish to thank J. LaVecchio, G. Buruzula, A. Wakabayashi, A. Pinkhasov, A. Clermont, M. Mulvey, C. Cahill and G. Sankaranarayanan for technical assistance, and E. Caniano for editorial contributions.

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T.J.S. and Y.-H.T. planned most of the experiments and wrote the paper. T.J.S. performed the majority of the experiments. P.H., T.L.H., L.E.M., R.X. and K.L.T. performed some of the animal and immunofluorescence experiments and/or provided research assistance. A.M.C. helped with the infrared thermography and provided valuable research materials. Y.M. and E.G. planned some of the experiments and contributed valuable research materials.

Corresponding author

Correspondence to Yu-Hua Tseng.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-13 and Supplementary Tables 1 and 2 which list primer sequences and expression levels of gene measured by quantitative real-time PCR. (PDF 1620 kb)

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Schulz, T., Huang, P., Huang, T. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013). https://doi.org/10.1038/nature11943

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