title: TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis.
abstract: Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
authors.forename: Hariom
authors.initials: H
authors.lastname: Yadav
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
authors.forename: Samir
authors.initials: S
authors.lastname: Devalaraja
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Chung
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854. Electronic address: ranes@mail.nih.gov.
authors.forename: Sushil G
authors.initials: SG
authors.lastname: Rane
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D005943:Gluconeogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2
keywords: AMP-activated kinase (AMPK); FOXO; SMAD transcription factor; diabetes; gluconeogenesis; liver; obesity; phosphoprotein phosphatase; transforming growth factor β (TGF-β)