Inhibition of Sam68 triggers adipose tissue browning.
Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Junlan
J
Zhou
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Min
M
Cheng
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Chan
C
Boriboun
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Mariam M
MM
Ardehali
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Changfei
C
Jiang
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Qinghua
Q
Liu
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Shuling
S
Han
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
David A
DA
Goukassian
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Yao-Liang
YL
Tang
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Ting C
TC
Zhao
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Ming
M
Zhao
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Lu
L
Cai
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Stéphane
S
Richard
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Raj
R
Kishore
Department of Medicine-Cardiology Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Tarry 14-721, Chicago, Illinois 60611, USA Department of Cardiology Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China Department of Biochemistry University of Ottawa, Ottawa, Ontario, Canada Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China College of Life Sciences, South-Central University for Nationalities, Wuhan, Hubei, China GeneSys Research Institute CardioVascular Research Center, Tufts University School of Medicine, Boston, Massachusetts, USA Department of Medicine Medical College of Georgia, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, USA Department of Surgery Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island, USA Kosair Children Hospital Research Institute Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA Lady Davis Institute for Medical Research McGill University, Montreal, Quebec, Canada Center for Translational Medicine Temple University School of Medicine, Philadelphia, Pennsylvania, USA g-qin@northwestern.edu.
Gangjian
G
Qin
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050154:Adiposity; D000818:Animals; D001522:Behavior, Animal; D048429:Cell Size; D060467:Disease Resistance; D002149:Energy Intake; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D007333:Insulin Resistance; D007473:Ion Channels / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009043:Motor Activity; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis; D000071256:Uncoupling Protein 1
D048868:Adaptor Proteins, Signal Transducing; D007473:Ion Channels; C513253:Khdrbs1 protein, mouse; D024101:Mitochondrial Proteins; D016601:RNA-Binding Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1
adipocyte; insulin; metabolism; obesity