title: Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes.
abstract: Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Hartig
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: David A
authors.initials: DA
authors.lastname: Bader
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Kathleen V
authors.initials: KV
authors.lastname: Abadie
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamed
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hamilton
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.affiliation: Department of Molecular and Cellular Biology (S.M.H., D.A.B., K.V.A., M.Mo., M.P.H., W.L., B.Y., L.C., D.D.M., M.A.M., S.E.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology (W.L.), Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435; Hans Popper Laboratory of Molecular Hepatology (M.Mu., M.T.), Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental Hepatology (M.W.), Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Diabetes and Endocrinology Research Center (L.C., M.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and the Baylor St Luke's Medical Center, Houston, Texas 77030; and Division of Radiation Oncology (S.E.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Sean E
authors.initials: SE
authors.lastname: McGuire
mesh_terms: D052438:Adipocytes, White / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9