title: Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling.
abstract: Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3(-)(/-) white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3(-/-) adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β activity might be an effective treatment strategy for obesity and diabetes.
authors: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Clinical Research Center, South Drive and Old Georgetown Road, Bethesda, MD 20892, USA.
authors: Hariom
authors: H
authors: Yadav
authors: Celia
authors: C
authors: Quijano
authors: Anil K
authors: AK
authors: Kamaraju
authors: Oksana
authors: O
authors: Gavrilova
authors: Rana
authors: R
authors: Malek
authors: Weiping
authors: W
authors: Chen
authors: Patricia
authors: P
authors: Zerfas
authors: Duan
authors: D
authors: Zhigang
authors: Elizabeth C
authors: EC
authors: Wright
authors: Christina
authors: C
authors: Stuelten
authors: Peter
authors: P
authors: Sun
authors: Scott
authors: S
authors: Lonning
authors: Monica
authors: M
authors: Skarulis
authors: Anne E
authors: AE
authors: Sumner
authors: Toren
authors: T
authors: Finkel
authors: Sushil G
authors: SG
authors: Rane
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000502:physiology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000517:prevention & control*; D004734:Energy Metabolism; D005951:Glucose Tolerance Test; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta