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

Haeusler, Rebecca A.; Hartil, Kirsten; Vaitheesvaran, Bhavapriya; Arrieta‐Cruz, Isabel; Knight, Colette; Cook, Joshua R.; Kammoun, Hélène L.; Febbraio, Mark A.; Gutiérrez‐Juárez, Roger; Kurland, Irwin J.; Accili, Domenico

doi:10.1038/ncomms6190

Cited by 164 publications

(203 citation statements)

References 48 publications

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“…We measured liver fat and glycogen content and found no difference between the groups in either; we did find liver fat content was positively associated with liver glycogen content. Animal studies have suggested in insulin resistance, portal hyperinsulinemia drives FoxO inactivation, leading to a decrease in the hepatic glucose 6-phosphatase catalytic subunit-to-glucokinase ratio and increased hepatic DNL, TG, diacylglycerol, and glycogen content (32). Our findings of higher hepatic DNL in HI compared with NI individuals are in line with this concept.…”

Section: Discussionsupporting

confidence: 81%

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

et al. 2016

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Resistance to the action of insulin affects fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver, and triglyceride export from the liver. To understand the metabolic consequences of hepatic fatty acid synthesis, partitioning, oxidation, and net liver fat content in the fasted and postprandial states, we used stable-isotope tracer methodologies to study healthy men and women with varying degrees of insulin resistance before and after consumption of a mixed meal. Subjects were classified as being normoinsulinemic (NI) (fasting plasma insulin <11.2 mU/L, n = 18) or hyperinsulinemic (HI) (fasting plasma insulin >11.2 mU/L, n = 19). Liver fat content was similar between HI and NI individuals, despite HI subjects having marginally more visceral fat. However, de novo lipogenesis was higher and fatty acid oxidation was lower in HI individuals compared with NI subjects. These data suggest that metabolic pathways promoting fat accumulation are enhanced in HI but, paradoxically, without any significant effect on liver fat content when observed in healthy people. This is likely to be explained by increased triglyceride secretion as observed by hypertriglyceridemia.

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Section: Discussionsupporting

confidence: 81%

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

et al. 2016

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“…In addition to maintaining robust expression of ␤-cell identity factors, FoxO1 appears to regulate the balance of glucose versus lipid utilization in islets as it does in liver (37). The key finding of the present study is the decrease of lipid utilization by purified islets in the presence of elevated glucose.…”

Section: Discussionsupporting

confidence: 49%

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

Kim-Muller

Kim

Fan

et al. 2016

Journal of Biological Chemistry

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Pancreatic ␤-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state ␤-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to ␤-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylationdependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo and decreased fatty acid oxidation ex vivo. Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild type by only ϳ2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for ␤-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects ␤-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in ␤-cells is beneficial to diabetes treatment.

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“…Previous studies indicate that FOXO1 overexpression in the liver increased hepatic triacylglycerol content, owing to increased triacylglycerol synthesis [40,41], while recent studies suggest that FOXO proteins suppress hepatic lipogenesis and triacylglycerol levels [42,43]. In this study we show that overexpression of FOXQ1 decreases hepatic and serum triacylglycerol contents in db/db and DIO mice.…”

Section: Discussionsupporting

confidence: 45%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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Aim/hypothesis Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. Methods We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. Results Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wildtype C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. Conclusions/interpretation FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.

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

Cited by 164 publications

References 48 publications

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

Fasting Plasma Insulin Concentrations Are Associated With Changes in Hepatic Fatty Acid Synthesis and Partitioning Prior to Changes in Liver Fat Content in Healthy Adults

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

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