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  • American Diabetes Association  (10)
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  • American Diabetes Association  (10)
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  • 1
    Online Resource
    Online Resource
    Foxo1-Ser253 Phosphorylation Regulates Glucose Homeostasis in Mice
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: The forkhead transcription factor Foxo1 is a key mediator in insulin signaling pathway that controls hepatic glucose production (HGP) and pancreatic beta-cell function. Upon activation of the protein kinase Akt, insulin promotes glycogen synthesis and inhibits gluconeogenesis in the liver, reducing blood glucose. We previously demonstrated human Foxo1-Ser256, an equivalent to mouse Foxo1-Ser253, is a key phosphorylation site for insulin and Akt suppression, promoting Foxo1 nuclear export and suppressing the expression of the target gene for liver gluconeogenesis. Here we investigated the role of Foxo1-Ser253 phosphorylation in control of glucose hemostasis in vivo, by generating Foxo1-S253A/A knock-in (KI) mice, in which Foxo1-Ser253 replaced by alanine (A mutation) that blocks phosphorylation. Foxo1-S253A/A mice displayed mild increases in feeding blood glucose and insulin level, but reductions in fasting blood glucose and glucagon concentration, as well as a decrease in the ratio of the number of pancreatic α-cells/β-cells per islet. Foxo1-S253A/A mice exhibited slight increases in insulin sensitivity but barely changed glucose uptake among tissues, and an enhanced energy expenditure. Further analyses indicate that Foxo1-S253A/A enhanced Foxo1 ability and promoted the effect of glucagon on HGP. This is the first report demonstrating that Foxo1-Ser253 phosphorylation status itself is sufficient to affect HGP and glucose homeostasis, as well as regulate the synthesis of insulin and glucagon in in vivo. Disclosure H. Yan: None. Y. Wu: None. Q. Pan: None. Z. Shen: None. H. Zheng: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories. Y. Sun: None. S. Guo: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1883-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    A Novel Mechanism by Foxo1 Phosphorylation Mediates Glucagon Signaling in Control of Glucose Homeostasis
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Glucagon increases hepatic glucose production (HGP) to maintain blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting metabolic enzymes for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation at Ser256 in human hepatocytes. Here we demonstrated glucagon promotes Foxo1 nuclear translocation and stability via protein kinase A (PKA)-dependent phosphorylation of Foxo1 at Ser276, serving as a novel mechanism of glucagon action in control of glucose homeostasis. In vitro protein kinase assay showed a direct phosphorylation of Foxo1 at Ser276 by PKA. Replacing Foxo1-Ser276 with alanine (S276A) or aspartate (S276D) reduced or increased Foxo1 stability in human hepatocytes, respectively. To establish the in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in mice, revealing the novel mechanism by which glucagon, via PKA-dependent phosphorylation of Foxo1 at Ser276, promotes Foxo1 nuclear localization, stability, and HGP. Thus, Foxo1-Ser276 is a potential target site for the control of Foxo1 bioactivity and associated metabolic diseases. Disclosure Y. Wu: None. H. Yan: None. Q. Pan: None. H. Zheng: None. S.A. Dahanayaka: None. Y. Sun: None. A. Zhou: None. L. Zhang: None. S. Guo: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1880-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 3
    Online Resource
    Online Resource
    Neuronal Deletion of Ghrelin Receptor Almost Completely Prevents Diet-Induced Obesity
    American Diabetes Association ; 2016
    In:  Diabetes Vol. 65, No. 8 ( 2016-08-01), p. 2169-2178
    Details
    In: Diabetes, American Diabetes Association, Vol. 65, No. 8 ( 2016-08-01), p. 2169-2178
    Abstract: Ghrelin signaling has major effects on energy and glucose homeostasis, but it is unknown whether ghrelin’s functions are centrally and/or peripherally mediated. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain and detectable in some peripheral tissues. To understand the roles of neuronal GHS-R, we generated a mouse line where Ghsr gene is deleted in all neurons using synapsin 1 (Syn1)-Cre driver. Our data showed that neuronal Ghsr deletion abolishes ghrelin-induced spontaneous food intake but has no effect on total energy intake. Remarkably, neuronal Ghsr deletion almost completely prevented diet-induced obesity (DIO) and significantly improved insulin sensitivity. The neuronal Ghsr-deleted mice also showed improved metabolic flexibility, indicative of better adaption to different fuels. In addition, gene expression analysis suggested that hypothalamus and/or midbrain might be the sites that mediate the effects of GHS-R in thermogenesis and physical activity, respectively. Collectively, our results indicate that neuronal GHS-R is a crucial regulator of energy metabolism and a key mediator of DIO. Neuronal Ghsr deletion protects against DIO by regulating energy expenditure, not by energy intake. These novel findings suggest that suppressing central ghrelin signaling may serve as a unique antiobesity strategy.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db15-1587
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2016
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  • 4
    Online Resource
    Online Resource
    Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 11 ( 2018-11-01), p. 2167-2182
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 11 ( 2018-11-01), p. 2167-2182
    Abstract: Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A–dependent phosphorylation of Foxo1 at Ser276. Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0674
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 5
    Online Resource
    Online Resource
    Glucagon Regulates Hepatic Mitochondrial Biogenesis and Function through Foxo1
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: The liver is an important organ regulating the energy metabolism, which is tightly governed by multiple hormones. Glucagon secreted from the alpha-cell of the pancreatic islets is a counterregulatory hormone contrary to the action of insulin. In addition to promoting hepatic glucose production, glucagon also plays multiple roles in the liver via its G protein-coupled glucagon receptor. In this study, we found that glucagon attenuated the mitochondrial oxygen consumption and ATP production in primary mouse hepatocytes and decreased hepatic mitochondrial copy numbers. To investigate the molecular mechanisms, we found that glucagon increased the expression of Foxo1 in protein level, which controls the expression of genes responsible for heme biosynthesis, frataxin (FXN) and uroporphyrinogen decarboxylase (UROD). The lower production of heme by glucagon impaired the integrity of electron transport chain (ETC), reducing the heme-dependent complex III (Uqcrc1) and complex IV (mt-Co1). Furthermore, glucagon downregulated mitochondrial transcription factor A (TFAM) and nuclear transcription factors 1 (NRF-1), impairing the mitochondrial biogenesis, which was abolished in Foxo1 deficient primary hepatocytes. These results demonstrate that glucagon inhibits mitochondrial biogenesis and function in a Foxo1-dependent manner. Disclosure W. Yang: None. H. Yan: None. Q. Pan: None. Z. Shen: None. S.A. Dahanayaka: None. C. Wu: None. Y. Sun: None. S. Guo: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-2442-PUB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 6
    Online Resource
    Online Resource
    1853-P: Transforming Growth Factor Beta 1 Acts as a Hepatokine in Control of Glucose and Energy Metabolism
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Liver and adipose tissue are crucial for blood glucose and energy homeostasis, while impaired regulation of hepatic glucose production (HGP) and energy expenditure contribute to hyperglycemia and excessive fat storage in type 2 diabetes mellitus. Hepatokines are proteins secreted by hepatocytes, and several hepatokines have been shown to directly affect glucose and energy expenditure. In this study, we investigated the role of transforming growth factor beta 1 (TGF-β1) in hepatocytes in regulating glucose and energy homeostasis. We generated the liver-specific TGF-β1 knockout mice and found that the mice exhibited lower blood glucose, increased hepatic insulin sensitivity compared with wild type (WT) control mice. Using the mouse primary hepatocytes, we found that TGF-β1 deletion impaired HGP and TGF-β1 treatment promoted protein kinase A (PKA) signaling and stimulated the nuclear translocation of FoxO1. Under high fat diet (HFD) treatment, hepatic TGF-β1 deficiency protected mice from HFD-induced obesity and insulin resistance, decreased HGP and improved energy expenditure. Moreover, we used hepatic insulin receptor substrate-1, 2 (IRS1, 2) knockout (DKO) mice and deleted the TGF-β1 gene in the liver of DKO mice. We found that hepatic TGF-β1 ablation prevented hyperglycemia and hyperinsulinemia in DKO mice. Deletion of TGF-β1 or neutralization of TGF-β1 with antibody significantly decreased HGP of DKO hepatocytes. Additionally, hepatic TGF-β1 ablation enhanced thermogenesis and inguinal white adipose tissue (iWAT) browning in DKO mice. These findings underscore an important role of hepatic TGF-β1 in contribution to systemic glucose and energy homeostasis. Thus, hepatic TGF-β1 may serve as a therapeutic target for control of glucose and energy homeostasis in insulin resistance and type 2 diabetes mellitus. Disclosure Q. Pan: None. Y. Chen: None. D. Kim: None. Z. Shen: None. W. Yang: None. X. Li: None. Y. Sun: None. S. Guo: None. Funding American Diabetes Association (1-15-CD-09 to S.G.)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1853-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 7
    Online Resource
    Online Resource
    Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. 2 ( 2019-02-01), p. 291-304
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. 2 ( 2019-02-01), p. 291-304
    Abstract: Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E2). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E2 on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E2 action on the suppression of gluconeogenesis. We further demonstrated that E2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)α–phosphoinositide 3-kinase–Akt–Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERα can be a potential approach to modulate glucose metabolism and prevent diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0638
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 8
    Online Resource
    Online Resource
    Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 9 ( 2023-09-01), p. 1193-1206
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 9 ( 2023-09-01), p. 1193-1206
    Abstract: Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-β1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-β1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-β1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-β1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-β1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-β1→Foxo1→TGF-β1 looping by deleting TGF-β1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-β1→Foxo1→TGF-β1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. Article Highlights Hepatic TGF-β1 levels are increased in obese humans and mice. Hepatic TGF-β1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-β1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase–mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-β1→Foxo1→TGF-β1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-0180
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 9
    Online Resource
    Online Resource
    Heme Oxygenase-1 Regulates Ferrous Iron and Foxo1 in Control of Hepatic Gluconeogenesis
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. 3 ( 2021-03-01), p. 696-709
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. 3 ( 2021-03-01), p. 696-709
    Abstract: The liver is a key player for maintaining glucose homeostasis. Excessive hepatic glucose production is considered to be a key for the onset of type 2 diabetes. The primary function of heme oxygenase-1 (HO1) is to catalyze the degradation of heme into biliverdin, ferrous iron, and carbon monoxide. Previous studies have demonstrated that the degradation of heme by HO1 in the liver results in mitochondrial dysfunction and drives insulin resistance. In this study, by overexpressing HO1 in hepatocytes and mice, we showed that HO1 promotes gluconeogenesis in a Foxo1-dependent manner. Importantly, HO1 overexpression increased the generation of ferrous iron in the liver, which further activates nuclear factor-κB and phosphorylates Foxo1 at Ser273 to enhance gluconeogenesis. We further assessed the role of HO1 in insulin-resistant liver-specific knockout of IRS1 and IRS2 genes (L-DKO) mice, which exhibit upregulation of HO1 in the liver and hepatic ferrous iron overload. HO1 knockdown by shRNA or treatment of iron chelator rescued the aberrant gluconeogenesis in L-DKO mice. In addition, we found that systemic iron overload promotes gluconeogenesis by activating the hepatic protein kinase A→Foxo1 axis. Thus, our results demonstrate the role of HO1 in regulating hepatic iron status and Foxo1 to control gluconeogenesis and blood glucose.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-0954
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 10
    Online Resource
    Online Resource
    1864-P: p38α MAPK Mediates Glucagon-Induced Hepatic Glucose Production through Phosphorylation of Foxo1 at Ser273
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Glucagon is involved in glucose homeostasis via triggering gluconeogenesis and glycogenolysis. In addition to activation of protein kinase A (PKA), p38α MAPK (p38) is activated by glucagon and promotes glucagon-induced hepatic glucose production. However, underlying mechanisms by which p38 mediates the effect of glucagon are not well elucidated. Previously, we established that glucagon increases the phosphorylation of Foxo1 at Ser273 via PKA to promote hepatic glucose production. In this study, we investigated the potential role of p38 in the action of glucagon by phosphorylation of Foxo1 at Ser273. Using the mouse primary hepatocytes, we showed that activation of p38 by glucagon promoted phosphorylation of Foxo1 at Ser273, which results in both increased stability and nuclear translocation of Foxo1. In vivo kinase assay shows that the active p38 enzyme increased the phosphorylation of Foxo1 at Ser273. Moreover, p38 promoted glucagon-induced PKA activity to increase the phosphorylation of Foxo1 at Ser273. Suppression of p38 by siRNA and SB203580 decreased hepatic glucose production by glucagon in control mouse primary hepatocytes; however, such an effect was diminished in the hepatocytes isolated from the Foxo1-S273D knock-in mice, where Foxo1-Ser273 was replaced by the aspartate mutation (D). In mice, we further showed that injection of p38 inhibitor SB203580 decreased the fasting blood glucose and hepatic glucose production in wild type control mice, while this effect was not observed in Foxo1-S273D mice. These results revealed the novel role of p38 in control of Foxo1 phosphorylation at Ser273 to regulate the action of glucagon in glucose homeostasis. Disclosure W. Yang: None. W. Ai: None. X. Li: None. Q. Pan: None. Z. Shen: None. Y. Chen: None. Y. Sun: None. S. Guo: None. Funding American Diabetes Association (1-15-CD-09 to S.G.); National Institutes of Health (R01DK095118)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1864-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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