title: Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans.
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.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Whittle
authors.affiliation: Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.|Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Meizi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
authors.forename: Vivian
authors.initials: V
authors.lastname: Peirce
authors.affiliation: 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.
authors.forename: Joana
authors.initials: J
authors.lastname: Relat
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.affiliation: Tsukuba Research Institute, Sekisui Medical Co. Ltd., Ryugasaki 301-0852, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ebinuma
authors.affiliation: Tsukuba Research Institute, Sekisui Medical Co. Ltd., Ryugasaki 301-0852, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Fukamachi
authors.affiliation: Center for Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Cardiovascular Center, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Murano
authors.affiliation: Center for Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tatsuno
authors.affiliation: Department of Hematology, Chiba University Hospital, Chiba 260-8677, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Department of Hematology, Chiba University Hospital, Chiba 260-8677, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakaseko
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Yanbian University, Yanji 133000, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Dermatology, Affiliated Hospital of Yanbian University, Yanji 133000, China.
authors.forename: Zhehu
authors.initials: Z
authors.lastname: Jin
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Department of Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Vienna 1030, Austria.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Schneider
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK.|Department of Cellular Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, Sakura 285-8741, Japan.|Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bujo
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015992:Body Mass Index; D015536:Down-Regulation; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000097:blood* / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000097:blood* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011973:Receptors, LDL / Q000097:blood* / Q000235:genetics; D022722:Thermogenesis
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse