Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans

Nat Commun. 2015 Nov 20:6:8951. doi: 10.1038/ncomms9951.

Andrew J Whittle ¹, Meizi Jiang ² ³, Vivian Peirce ¹, Joana Relat ⁴, Sam Virtue ¹, Hiroyuki Ebinuma ⁵, Isamu Fukamachi ⁵, Takashi Yamaguchi ⁶, Mao Takahashi ⁷, Takeyoshi Murano ², Ichiro Tatsuno ⁶, Masahiro Takeuchi ⁸, Chiaki Nakaseko ⁸, Wenlong Jin ⁹, Zhehu Jin ¹⁰, Mark Campbell ¹, Wolfgang J Schneider ¹¹, Antonio Vidal-Puig ¹ ¹², Hideaki Bujo ² ³

Affiliations

1 University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
2 Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
3 Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
4 Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, and Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.
5 Tsukuba Research Institute, Sekisui Medical Co. Ltd., Ryugasaki 301-0852, Japan.
6 Center for Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
7 Cardiovascular Center, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
8 Department of Hematology, Chiba University Hospital, Chiba 260-8677, Japan.
9 Department of Endocrinology, Affiliated Hospital of Yanbian University, Yanji 133000, China.
10 Department of Dermatology, Affiliated Hospital of Yanbian University, Yanji 133000, China.
11 Department of Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Vienna 1030, Austria.
12 Department of Cellular Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

PMID: 26584636 DOI: 10.1038/ncomms9951

Abstract

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFβ signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.

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