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TGF‐beta/SMAD3 SIGNALING REGULATES HEPATIC GLUCOSE METABOLISM
Author(s) -
Yadav Hariom,
Gavrilova Oksana,
Lonning Scott,
Rane Sushil G
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1117.6
Subject(s) - insulin resistance , endocrinology , medicine , steatosis , fatty liver , gluconeogenesis , carbohydrate metabolism , insulin receptor , insulin , beta oxidation , type 2 diabetes , biology , diabetes mellitus , metabolism , disease
Abnormal liver function, such as hepatic steatosis, hepatic insulin resistance and increased hepatic glucose production is frequently associated with metabolic disorders such as insulin resistance, obesity and diabetes. Various signaling pathways are involved in regulation of hepatic glucose metabolism. Here, we describe a novel role of TGF‐β signaling is in control of hepatic gluconeogenesis. Interestingly, we find that circulating TGF‐β levels are significantly increased in obese human subjects, Lep ob/ob mice and high‐fat‐diet (HFD)‐induced obese (DIO) mice. This is accompanied with enhanced Smad3 activity and hepatic insulin resistance and adiposity. Importantly, Smad3 −/− mice display enhanced hepatic insulin sensitivity and significantly increased glucose uptake in liver tissues. Moreover, we detect significantly reduced hepatic endogenous glucose production in response to exogenous insulin and pyruvate challenge. Surprisingly, when challenged with high fat diet (HFD), Smad3 −/− mice are protected from insulin resistance, obesity and hepatic steatosis. Further, treatment of diabetes susceptible Lep ob/ob and DIO mice with an anti‐TGF‐β neutralizing antibody results in improved hepatic insulin sensitivity and resolution of hepatic steatosis. We discover that TGF‐β/Smad3 signaling mediates the beneficial effects by modulating fatty acid β‐oxidation genes and energy sensing molecules, specifically, the adenosine mono phosphate kinases (AMPKs) and the downstream target acetyl CoA carboxylase (ACC). We conclude that TGF‐β/Smad3 signaling blockade enhances energy metabolism in hepatic tissues and ameliorates diet‐induced obesity and diabetes. We believe that these findings support the investigational use of anti‐TGF‐β/Smad3 approaches for management and therapy of diabetes and obesity.