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Integrated Control of Hepatic Lipogenesis vs. Glucose Production Requires FoxO Transcription Factors

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 model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 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 vs. 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. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4. Liver tissue samples were collected from hepatocyte- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice after fasting (22 h) or refeeding (4 h). Gene expression was analyzed by microarray. Mice were on a mixed background of C57BL/6J and 129.

ORGANISM(S): Mus musculus

SUBMITTER: Rebecca Haeusler

PROVIDER: E-GEOD-60527 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Integrated Control of Hepatic Lipogenesis vs. Glucose Production Requires FoxO Transcription Factors

Project description: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 model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 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 vs. 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. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4.

2014-08-20 | GSE60527 | GEO

Disruption of the phosphate transporter Pit1 in hepatocytes improves glucose metabolism and insulin signalling by modulating the USP7/IRS1 interaction.

Project description:The liver plays a central role in whole-body lipid and glucose homeostasis. Increasing dietary fat intake results in increased hepatic fat deposition, which is associated with a risk for development of insulin resistance and type 2 diabetes. In this study, we demonstrate a role for the phosphate inorganic transporter 1 (PiT1/SLC20A1) in regulating metabolism. Specific knockout of Pit1 in hepatocytes significantly improved glucose tolerance and insulin sensitivity, enhanced insulin signalling, and decreased hepatic lipogenesis. We identified USP7 as a PiT1 binding partner and demonstrated that Pit1 deletion inhibited USP7/IRS1 dissociation upon insulin stimulation. This prevented IRS1 ubiquitination and its subsequent proteasomal degradation. As a consequence delayed insulin negative feedback loop and sustained insulin signalling were observed. Moreover, PiT1-deficient mice were protected against high fat diet-induced obesity and diabetes. Our findings indicate that PiT1 has potential as a therapeutic target in the context of metabolic syndrome, obesity, and diabetes.

2016-08-25 | E-MTAB-4989 | biostudies-arrayexpress

Insulin and IGF-1 Receptors Regulate Complex-I Dependent Mitochondrial Bioenergetics and Supercomplexes via FoxOs in Muscle

Project description:Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (MIRKO) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (QKO). Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in MIGIRKO muscle, and these were reversed with FoxO knockout. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.

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Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients [transcriptome analysis]

Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance. To better understand the molecular mechanisms underlying the development of hepatic insulin resistance and type 2 diabetes at a molecular level, we performed a genome-wide methylome and transcriptome analysis of liver from non-obese metabolically healthy, obese non-diabetic and obese type 2 diabetic patients. Distinct DNA methylation and gene expression profiles were identified in liver from the obese and type 2 diabetic patients compared with the non-obese participants.

2016-03-08 | E-GEOD-64998 | biostudies-arrayexpress

Proteomic and phosphoproteomic analysis of PKCe KO

Project description:Activation of protein kinase C epsilon (PKCε) in the liver has been widely associated with hepatic insulin resistance. PKCε is proposed to inhibit insulin signalling through phosphorylation of the insulin receptor. We have tested this directly by breeding PKCε floxed mice with mice expressing Cre recombinase under the control of the cytomegalovirus, albumin or adiponectin promoters to generate global, liver- and adipose tissue-specific PKCε knockout (KO) mice. Global deletion of PKCε recapitulated the benefits for diet-induced glucose intolerance that we previously described using conventional PKCε KO mice. However, we did not detect PKCε-dependent alterations in hepatic insulin receptor phosphorylation. Furthermore, liver-specific KO mice were not protected against diet-induced glucose intolerance or insulin resistance determined by euglycemic clamp. In contrast, adipose tissue-specific KO mice exhibited improved glucose tolerance and mildly increased hepatic triglyceride storage, but no change in liver insulin sensitivity. Phosphoproteomic analysis of insulin signalling in PKCε KO adipocytes revealed no defect in the canonical INSR/AKT/mTOR pathways. However, PKCε KO resulted in changes in phosphorylation of several proteins associated with the endosome and cell junctions suggesting regulation in secretory pathways and a potential role of PKCε in endocrine function. Indeed, RNA-seq analysis revealed adipose-tissue PKCε-dependent changes in the hepatic expression of several genes linked to glucose homeostasis and hepatic lipid metabolism. The primary effect of PKCε on glucose homeostasis is therefore not exerted directly in the liver as currently assumed. However, PKCε in adipose tissue modulates glucose tolerance and is involved in crosstalk with the liver that affects gene expression and lipid accumulation.

2018-10-04 | PXD010212 | Pride

The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase

Project description:Strong associations exist between branched chain amino acids (BCAA) and dysregulated glucose and lipid metabolism, but the underlying mechanisms are not well understood. Here we report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulate branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Overexpression of BDK in liver of lean rats increased ACL phosphorylation and activated de novo lipogenesis. Moreover, BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding and expression of the ChREBP transcription factor. These studies identify BDK and PPM1K as a regulatory node that integrates BCAA, glucose, and lipid metabolism via reciprocal regulation of BCKDH and ACL. Modulation of this node relieves key disease phenotypes in a genetic model of severe obesity and metabolic dysfunction.

2018-05-18 | PXD009122 | Pride

Hepatocyte Deletion of Triglyceride-Synthesis Enzyme DGAT2 Reduces Steatosis without Increasing Inflammation or Fibrosis

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and reprepresents a huge public health problem owing to its propensity to progress to non-alcoholic steatohepatitis (NASH), fibrosis, and liver failure. The lipids stored in hepatic steatosis are primarily triglycerides (TGs) synthesized by two acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, with DGAT2 being linked to storage of fatty acids from de novo lipogenesis, a process that is increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and the progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specfici Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction of steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduced diet-induced hepatic steatosis and supports the development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.

2020-05-26 | PXD013423 | Pride

Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients [methylome analysis]

2016-03-08 | GSE65057 | GEO

Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients [transcriptome analysis]

2016-03-08 | GSE64998 | GEO

Exercise prevents substrate overload of liver mitochondria by modification of the compensatory responses during chronic overnutrition

Project description:Exercise training is a potent treatment of NAFLD and hepatic insulin resistance. Here we provide molecular information about the hepatic mitochondrial metabolism in mice when chronic overnutrition (high-energy diet (HED) for 6 weeks) is combined with exercise training. Training reduced the hepatic triacylglycerol content, fasting insulin, and reversed glucose intolerance. Training modified the hepatic mitochondrial proteome with a decrease in enzymes related to pyruvate metabolism and entry of acetyl-CoA into the TCA cycle. Transcriptome data revealed down-regulation of glucose oxidation and lipogenesis. The mitochondrial respiratory capacity of trained HED-fed mice is increased despite reduced content of complex I. Training decreased diacylglycerol species and JNK phosphorylation, both of which can induce insulin resistance. Increased mitochondrial mass and oxidative capacity of the trained muscle further unburdens the liver from substrate overload. Together, when high fat and carbohydrate intake in mice is accompanied by exercise, the decline of mitochondrial function and insulin resistance can be prevented by modification of mitochondrial acetyl-CoA metabolism.

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