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Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.

Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta-Cruz I, Knight CM, Cook JR, Kammoun HL, Febbraio MA, Gutierrez-Juarez R, Kurland IJ, Accili D - Nat Commun (2014)

Bottom Line: A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation.We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism.Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA.

ABSTRACT
Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver-specific ablation of three FoxOs (L-FoxO1,3,4) prevents the induction of glucose-6-phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

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Lipogenic gene expression during F–RF in chow–fed C57BL/6J mice and proposed physiologic model (a) Comparison of Gck, Elovl6, and Pklr expression. For each gene, the 24–hr fasting time point is set equal to 1. Elovl6 and Pklr are plotted using the vertical axis on the left, and Gck is plotted using the vertical axis on the right. n = 5 per group. Black and white bars indicate the dark/light cycle. (b) Model. Earlier data suggested parallel action of insulin through FoxO to regulate HGP, and through Srebp–1c to regulate DNL. We propose a new model, whereby: insulin acts first at low levels and early time points through FoxOs to reduce HGP and initiate postprandial DNL by reducing the G6pc/Gck ratio; and second at high levels and late time points through Srebp–1c to amplify DNL.
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Figure 3: Lipogenic gene expression during F–RF in chow–fed C57BL/6J mice and proposed physiologic model (a) Comparison of Gck, Elovl6, and Pklr expression. For each gene, the 24–hr fasting time point is set equal to 1. Elovl6 and Pklr are plotted using the vertical axis on the left, and Gck is plotted using the vertical axis on the right. n = 5 per group. Black and white bars indicate the dark/light cycle. (b) Model. Earlier data suggested parallel action of insulin through FoxO to regulate HGP, and through Srebp–1c to regulate DNL. We propose a new model, whereby: insulin acts first at low levels and early time points through FoxOs to reduce HGP and initiate postprandial DNL by reducing the G6pc/Gck ratio; and second at high levels and late time points through Srebp–1c to amplify DNL.

Mentions: Our data suggests that derepression of Gck may be an exquisitely insulin-sensitive mechanism to activate DNL23,24,35 independently of canonical lipogenic pathways. We examined this in more detailin C57BL/6J mice during F–RF. Both Elovl6 (Srebp–1c target) and Pklr (Chrebp target) were reduced during fasting and increased after refeeding, as expected (Fig. 3a). In contrast, the fluctuations of Gck were greater during F–RF, and peaked within 1–hr of refeeding, hours before Srebp–1c and Chrebp targets. We confirmed that Gck protein was induced within 1 hr of refeeding (Supplementary Fig. 3a).


Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.

Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta-Cruz I, Knight CM, Cook JR, Kammoun HL, Febbraio MA, Gutierrez-Juarez R, Kurland IJ, Accili D - Nat Commun (2014)

Lipogenic gene expression during F–RF in chow–fed C57BL/6J mice and proposed physiologic model (a) Comparison of Gck, Elovl6, and Pklr expression. For each gene, the 24–hr fasting time point is set equal to 1. Elovl6 and Pklr are plotted using the vertical axis on the left, and Gck is plotted using the vertical axis on the right. n = 5 per group. Black and white bars indicate the dark/light cycle. (b) Model. Earlier data suggested parallel action of insulin through FoxO to regulate HGP, and through Srebp–1c to regulate DNL. We propose a new model, whereby: insulin acts first at low levels and early time points through FoxOs to reduce HGP and initiate postprandial DNL by reducing the G6pc/Gck ratio; and second at high levels and late time points through Srebp–1c to amplify DNL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197140&req=5

Figure 3: Lipogenic gene expression during F–RF in chow–fed C57BL/6J mice and proposed physiologic model (a) Comparison of Gck, Elovl6, and Pklr expression. For each gene, the 24–hr fasting time point is set equal to 1. Elovl6 and Pklr are plotted using the vertical axis on the left, and Gck is plotted using the vertical axis on the right. n = 5 per group. Black and white bars indicate the dark/light cycle. (b) Model. Earlier data suggested parallel action of insulin through FoxO to regulate HGP, and through Srebp–1c to regulate DNL. We propose a new model, whereby: insulin acts first at low levels and early time points through FoxOs to reduce HGP and initiate postprandial DNL by reducing the G6pc/Gck ratio; and second at high levels and late time points through Srebp–1c to amplify DNL.
Mentions: Our data suggests that derepression of Gck may be an exquisitely insulin-sensitive mechanism to activate DNL23,24,35 independently of canonical lipogenic pathways. We examined this in more detailin C57BL/6J mice during F–RF. Both Elovl6 (Srebp–1c target) and Pklr (Chrebp target) were reduced during fasting and increased after refeeding, as expected (Fig. 3a). In contrast, the fluctuations of Gck were greater during F–RF, and peaked within 1–hr of refeeding, hours before Srebp–1c and Chrebp targets. We confirmed that Gck protein was induced within 1 hr of refeeding (Supplementary Fig. 3a).

Bottom Line: A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation.We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism.Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA.

ABSTRACT
Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver-specific ablation of three FoxOs (L-FoxO1,3,4) prevents the induction of glucose-6-phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

Show MeSH
Related in: MedlinePlus