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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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Glucose parameters in L–FoxO1,3,4 mice. (a) Percentage of pups surviving to weaning at 21 days. n = 70 control and 24 L–FoxO1,3,4 pups. ***P < 0.001 by Fisher’s exact test. These numbers may underestimate the true mortality of L–FoxO1,3,4 pups; at genotyping (day 9) they are already present at less than Mendelian ratios7. (b–d) During hyperinsulinemic–euglycemic clamp (n = 8 controls, 6 L–FoxO 1,3,4): (b) glucose infusion rate (GIR); (c) rate of glucose disposal (Rd); (d) glucose production (GP) **P < 0.01 by Student’s t test (2–tailed). (e–i) Liver gene expression and glycogen content during F–RF time course (n = 4–7, exact n for each time point and genotype listed in materials & methods): (e) G6pc expression; (f) liver glycogen; (g) Slc37a4, encoding the glucose 6–phosphate transporter; (h) Gck; (i) G6pc/Gckratio. *** P < 0.001, **P < 0.01, *P< 0.05 for control vs. L–FoxO1,3,4 mice by Student’s t test (2–tailed). Black and white bars indicate the dark/light cycle. (j) Correlation between glucose levels and the G6pc/Gck ratio in pups at P2. Data are mean ± s.e.m.
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Figure 1: Glucose parameters in L–FoxO1,3,4 mice. (a) Percentage of pups surviving to weaning at 21 days. n = 70 control and 24 L–FoxO1,3,4 pups. ***P < 0.001 by Fisher’s exact test. These numbers may underestimate the true mortality of L–FoxO1,3,4 pups; at genotyping (day 9) they are already present at less than Mendelian ratios7. (b–d) During hyperinsulinemic–euglycemic clamp (n = 8 controls, 6 L–FoxO 1,3,4): (b) glucose infusion rate (GIR); (c) rate of glucose disposal (Rd); (d) glucose production (GP) **P < 0.01 by Student’s t test (2–tailed). (e–i) Liver gene expression and glycogen content during F–RF time course (n = 4–7, exact n for each time point and genotype listed in materials & methods): (e) G6pc expression; (f) liver glycogen; (g) Slc37a4, encoding the glucose 6–phosphate transporter; (h) Gck; (i) G6pc/Gckratio. *** P < 0.001, **P < 0.01, *P< 0.05 for control vs. L–FoxO1,3,4 mice by Student’s t test (2–tailed). Black and white bars indicate the dark/light cycle. (j) Correlation between glucose levels and the G6pc/Gck ratio in pups at P2. Data are mean ± s.e.m.

Mentions: We found that 30% of L–FoxO1,3,4 mice die prior to weaning (Fig. 1a), possibly due to fatal postnatal hypoglycemia (Supplementary Fig. 1a)7. Surviving adult L–FoxO1,3,4 mice presumably have the most robust compensatory mechanisms, but still showed low glucose and insulin during day time ad libitum feeding, and hypoglycemia after prolonged fasting (Supplementary Fig. 1b–c)7,18. In hyperinsulinemic–euglycemic clamps, L–FoxO1,3,4 mice required double the glucose infusion rate of controls (Fig. 1b). There was no significant difference in glucose disposal, but L–FoxO1,3,4 mice showed ~60% reduction in HGP (Fig. 1c–d).


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)

Glucose parameters in L–FoxO1,3,4 mice. (a) Percentage of pups surviving to weaning at 21 days. n = 70 control and 24 L–FoxO1,3,4 pups. ***P < 0.001 by Fisher’s exact test. These numbers may underestimate the true mortality of L–FoxO1,3,4 pups; at genotyping (day 9) they are already present at less than Mendelian ratios7. (b–d) During hyperinsulinemic–euglycemic clamp (n = 8 controls, 6 L–FoxO 1,3,4): (b) glucose infusion rate (GIR); (c) rate of glucose disposal (Rd); (d) glucose production (GP) **P < 0.01 by Student’s t test (2–tailed). (e–i) Liver gene expression and glycogen content during F–RF time course (n = 4–7, exact n for each time point and genotype listed in materials & methods): (e) G6pc expression; (f) liver glycogen; (g) Slc37a4, encoding the glucose 6–phosphate transporter; (h) Gck; (i) G6pc/Gckratio. *** P < 0.001, **P < 0.01, *P< 0.05 for control vs. L–FoxO1,3,4 mice by Student’s t test (2–tailed). Black and white bars indicate the dark/light cycle. (j) Correlation between glucose levels and the G6pc/Gck ratio in pups at P2. Data are mean ± s.e.m.
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Figure 1: Glucose parameters in L–FoxO1,3,4 mice. (a) Percentage of pups surviving to weaning at 21 days. n = 70 control and 24 L–FoxO1,3,4 pups. ***P < 0.001 by Fisher’s exact test. These numbers may underestimate the true mortality of L–FoxO1,3,4 pups; at genotyping (day 9) they are already present at less than Mendelian ratios7. (b–d) During hyperinsulinemic–euglycemic clamp (n = 8 controls, 6 L–FoxO 1,3,4): (b) glucose infusion rate (GIR); (c) rate of glucose disposal (Rd); (d) glucose production (GP) **P < 0.01 by Student’s t test (2–tailed). (e–i) Liver gene expression and glycogen content during F–RF time course (n = 4–7, exact n for each time point and genotype listed in materials & methods): (e) G6pc expression; (f) liver glycogen; (g) Slc37a4, encoding the glucose 6–phosphate transporter; (h) Gck; (i) G6pc/Gckratio. *** P < 0.001, **P < 0.01, *P< 0.05 for control vs. L–FoxO1,3,4 mice by Student’s t test (2–tailed). Black and white bars indicate the dark/light cycle. (j) Correlation between glucose levels and the G6pc/Gck ratio in pups at P2. Data are mean ± s.e.m.
Mentions: We found that 30% of L–FoxO1,3,4 mice die prior to weaning (Fig. 1a), possibly due to fatal postnatal hypoglycemia (Supplementary Fig. 1a)7. Surviving adult L–FoxO1,3,4 mice presumably have the most robust compensatory mechanisms, but still showed low glucose and insulin during day time ad libitum feeding, and hypoglycemia after prolonged fasting (Supplementary Fig. 1b–c)7,18. In hyperinsulinemic–euglycemic clamps, L–FoxO1,3,4 mice required double the glucose infusion rate of controls (Fig. 1b). There was no significant difference in glucose disposal, but L–FoxO1,3,4 mice showed ~60% reduction in HGP (Fig. 1c–d).

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