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Resolving the Paradox of Hepatic Insulin Resistance

  • Dominic Santoleri
    Affiliations
    Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Paul M. Titchenell
    Correspondence
    Correspondence Address correspondence to: Paul M. Titchenell, PhD, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. fax: (215) 898-5408.
    Affiliations
    Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Open AccessPublished:November 03, 2018DOI:https://doi.org/10.1016/j.jcmgh.2018.10.016
      Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin’s control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway.

      Keywords

      Abbreviations used in this paper:

      ChREBP (carbohydrate response element binding protein), FFA (free fatty acid), Gck (glucokinase), GSK3 (glycogen synthase kinase 3), GYS2 (glycogen synthase), HGP (hepatic glucose production), IRS (insulin-receptor substrate), LIRKO (liver insulin resistant knockout mice), mTORC (mechanistic target of rapamycin complex), NAFLD (nonalcoholic fatty liver disease), PIP3 (phosphatidylinositol (3,4,5)-trisphosphate), PI3K (phosphoinositide-3-phosphate kinase), PTEN (phosphatase and tensin homolog), SCAP (SREBP cleavage-activating protein), SREBP1c (sterol regulatory element binding protein 1c), TAG (triacylglycerol), T2DM (type II diabetes mellitus), TSC (tuberous sclerosis complex), VLDL (very-low-density lipoprotein)
      This review describes the signaling pathways involved in the regulation of liver metabolism by insulin. In addition, it explores the molecular mechanisms underlying hepatic insulin resistance, highlighting the contribution of intrahepatic and extrahepatic pathways.
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      Hepatic Insulin Signaling and Lipid Metabolism

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      Figure thumbnail gr1
      Figure 1PI3K/Akt signaling in hepatocytes. Insulin binds to and activates the insulin receptor on the liver surface after a meal. After activation, the receptor recruits and activates IRS, which then activates PI3K. PI3K phosphorylates the signaling lipid molecule PIP2 into PIP3 in a process that is opposed by PTEN. PIP3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which phosphorylates Akt at Thr308. To fully activate Akt, mTORC2 also must phosphorylate it at Ser473. From Akt, different pathways for controlling glucose and lipid homeostasis branch out. Glycogen synthesis is induced through Akt inhibition of GSK3. In addition, Akt can promote glycogen synthesis in a manner independent of GSK3, such as activation of GYS2 by glucose-6-phosphate (G6P). Akt inhibition of TSC activates mTORC1, which in turn activates the lipogenic gene program through activation of SREBP1c and Gck, which phosphorylates glucose to G6P, which feeds into glycolysis and glycogen synthesis. In addition, G6P activates ChREBP, which activates lipogenesis along with SREBP1c. Akt inhibits FoxO1, resulting in an inhibition of gluconeogenesis by suppressing expressing of the proteins glucose-6-phosphatase (G6pc) and Pck1. Externally, FFAs can promote gluconeogenesis and contribute to insulin resistance by being taken up by the liver and converted to Acetyl-CoA, which activates pyruvate carboxylase.
      Because several studies support an obligate role of hepatic insulin action to regulate lipid metabolism, defining the mechanisms downstream of Akt are essential for understanding the pathogenesis of NAFLD during insulin resistance. One major downstream target of Akt is the mechanistic target of rapamycin complex 1 (mTORC1). Akt activates mTORC1 through inhibition of the tuberous sclerosis complex (TSC), a protein that inhibits mTORC1 localization to and activation at the lysosome through inhibition of Rheb
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      The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals.
      Therefore, SREBP1c is a necessary factor in lipogenic gene expression and in the development of fatty liver.
      In addition to SREBP1c, carbohydrate response element binding protein (ChREBP) is a well-studied, glucose-responsive transcription factor that may play a role in controlling hepatic lipid metabolism. Glucose-6-phosphate is the key activator of ChREBP, facilitating its migration to the nucleus
      • Dentin R.
      • Tomas-Cobos L.
      • Foufelle F.
      • Leopold J.
      • Girard J.
      • Postic C.
      • Ferré P.
      Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.
      (Figure 1). Because insulin signaling enhances glucose uptake in the liver, ChREBP becomes activated. As a transcription factor, ChREBP activates similar lipogenic genes to SREBP1c, although its roles in insulin sensitivity remain controversial. Normal mice with ChREBP deleted globally show decreased lipogenesis as well as mild insulin resistance.
      • Iizuka K.
      • Bruick R.K.
      • Liang G.
      • Horton J.D.
      • Uyeda K.
      Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.
      However, ChREBP deficiency in obese mice also results in decreased lipid accumulation and improved insulin sensitivity.
      • Iizuka K.
      • Miller B.
      • Uyeda K.
      Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice.
      Moreover, increased ChREBP is sufficient to increase fatty liver progression because overexpression of hepatic ChREBP in mice results in steatosis.
      • Benhamed F.
      • Denechaud P.D.
      • Lemoine M.
      • Robichon C.
      • Moldes M.
      • Bertrand-Michel J.
      • Ratziu V.
      • Serfaty L.
      • Housset C.
      • Capeau J.
      • Girard J.
      • Guillou H.
      • Postic C.
      The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans.
      Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.
      • Hurtado Del Pozo C.
      • Vesperinas-García G.
      • Rubio M.Á.
      • Corripio-Sánchez R.
      • Torres-García A.J.
      • Obregon M.J.
      • Calvo R.M.
      ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity.
      Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbohydrate diet, but had no effect on lipogenesis and lipogenic gene expression under normal chow.
      • Jois T.
      • Chen W.
      • Howard V.
      • Harvey R.
      • Youngs K.
      • Thalmann C.
      • Saha P.
      • Chan L.
      • Cowley M.A.
      • Sleeman M.W.
      Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice.
      Hepatic deletion of ChREBP in mice following a high-carbohydrate diet caused a reduction in glycolytic and lipogenic gene expression, including a partial loss of SREBP1c expression. Restoration of nuclear SREBP1c signaling in liver-specific ChREBP knockout mice increased the expression of the lipogenic genes ACLY, ACC2, SCD1, and GPAT, but failed to restore them to control levels, suggesting that both SREBP1c and ChREBP are needed to fully regulate lipogenesis in the liver. In addition, SREBP1c overexpression had no effect on restoring glycolytic gene expression. Moreover, overexpressing ChREBP was not sufficient to regain any significant lipogenic gene induction in mice lacking SREBP after SCAP deletion, showing that SREBP is required for the induction of lipogenic expression.
      • Linden A.G.
      • Li S.
      • Choi H.Y.
      • Fang F.
      • Fukasawa M.
      • Uyeda K.
      • Hammer R.E.
      • Horton J.D.
      • Engelking L.J.
      • Liang G.
      Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice.
      The interplay between ChREBP and SREBP1c in regulating lipogenic gene expression helps ensure that the liver does not initiate lipid synthesis unless both glucose and insulin are present, and future studies will continue to unravel their coordinated regulation of lipid synthesis.
      Alongside de novo lipogenesis, insulin action also regulates lipid homeostasis by regulating triacylglycerol (TAG) secretion from the liver via very-low-density lipoprotein (VLDL)-TAG export. Enhanced secretion of VLDL-TAG is another hallmark of people with insulin-resistant conditions, such as obesity or NAFLD.
      • Poulsen M.K.
      • Nellemann B.
      • Stødkilde-Jørgensen H.
      • Pedersen S.B.
      • Grønbæk H.
      • Nielsen S.
      Impaired insulin suppression of VLDL-triglyceride kinetics in nonalcoholic fatty liver disease.
      • Lewis G.F.
      • Uffelman K.D.
      • Szeto L.W.
      • Steiner G.
      Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL ApoB production in normal weight and obese individuals.
      In particular, a failure of insulin to facilitate degradation of apolipoprotein B, a major protein in VLDL synthesis, as well as increased levels of FFAs and increased lipogenesis in insulin-resistant disorders, are believed to stimulate VLDL secretion.
      • Ginsberg H.N.
      • Zhang Y.-L.
      • Hernandez-ono A.
      Metabolic syndrome : focus on dyslipidemia.
      The last point potentially carries the most weight because it may not be insulin resistance per se that stimulates VLDL secretion, but instead the hyperinsulinemia that results from it. Studies in rats have shown that hyperinsulinemia stimulates TAG turnover and VLDL secretion.
      • Steiner G.
      • Haynes F.J.
      • Yoshino G.
      • Vranic M.
      Hyperinsulinemia and in vivo very-low-density lipoprotein-triglyceride kinetics.
      In addition, disrupting insulin signaling in mouse livers by deleting Akt or the insulin receptor reduces VLDL secretion.
      • Han S.
      • Liang C.P.
      • Westerterp M.
      • Senokuchi T.
      • Welch C.L.
      • Wang O.
      • Matsumoto M.
      • Accili D.
      • Tall A.R.
      Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.
      Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial part of VLDL synthesis and secretion.
      • Quinn W.J.
      • Wan M.
      • Shewale S.V.
      • Gelfer R.
      • Rader D.J.
      • Birnbaum M.J.
      • Titchenell P.M.
      MTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.
      As such, insulin regulation of VLDL-TAG secretion is complex and the coordinated control of apolipoproteins, phospholipids, and TAG synthesis are essential for proper control of VLDL-TAG secretion.
      In addition to mTORC1, strong evidence exists for FoxO1’s ability to regulate liver lipid synthesis downstream of hepatic Akt signaling. When activated by insulin, Akt phosphorylates FoxO1 and inactivates it via phosphorylation, leading to nuclear exclusion
      • Gross D.N.
      • Wan M.
      • Birnbaum M.J.
      The role of FOXO in the regulation of metabolism.
      (Figure 1). Transgenic mice with livers expressing a constitutively active form of FoxO1 that cannot be phosphorylated by Akt due to its three active serine residues being mutated to alanines, FoxoAAA, fail to initiate transcription of lipogenic genes after feeding, leading to a reduction in lipogenesis and triglyceride secretion.
      • Zhang W.
      • Patil S.
      • Chauhan B.
      • Guo C.
      • Powell D.R.
      • Le J.
      • Klotsas A.
      • Matika R.
      • Xiao X.
      • Franks R.
      • Heidenreich K.A.
      • Sajan M.P.
      • Farese R.V.
      • Stolz D.B.
      • Tso P.
      • Koo S.H.
      • Montminy M.
      • Unterman T.G.
      FoxO1 regulates multiple metabolic pathways in the liver effects on gluconeogenic, glycolytic, and lipogenic gene expression.
      • Zhang W.
      • Bu S.Y.
      • Mashek M.T.
      • O-Sullivan I.
      • Sibai Z.
      • Khan S.A.
      • Ikayeva O.
      • Newgard C.B.
      • Mashek D.G.
      • Unterman T.G.
      Integrated regulation of hepatic lipid and glucose metabolism by ATGL and FoxO proteins.
      Conversely, deletion of all FoxO isoforms from the liver activates lipogenic gene expression and induces de novo lipogenesis correlating with hepatic steatosis.
      • Haeusler R.A.
      • Hartil K.
      • Vaitheesvaran B.
      • Arrieta-Cruz I.
      • Knight C.M.
      • Cook J.R.
      • Kammoun H.L.
      • Febbraio M.A.
      • Gutierrez-Juarez R.
      • Kurland I.J.
      • Accili D.
      Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.
      Because FoxO1 is thought to be a transcriptional activator, the specific mechanisms governing its inhibition of lipogenesis is unclear. However, recent studies have argued that FoxO1 directly represses the transcription of SREBP1c.
      • Deng X.
      • Zhang W.
      • O-Sullivan I.S.
      • Williams J.B.
      • Dong Q.
      • Park E.A.
      • Raghow R.
      • Unterman T.G.
      • Elam M.B.
      FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c.
      In addition, FoxO1 has been implicated in regulating the expression of glucokinase (Gck) through a repression mechanism mediated by Sin3a and Sin3b
      • Haeusler R.A.
      • Hartil K.
      • Vaitheesvaran B.
      • Arrieta-Cruz I.
      • Knight C.M.
      • Cook J.R.
      • Kammoun H.L.
      • Febbraio M.A.
      • Gutierrez-Juarez R.
      • Kurland I.J.
      • Accili D.
      Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.
      • Hirota K.
      • Sakamaki J.I.
      • Ishida J.
      • Shimamoto Y.
      • Nishihara S.
      • Kodama N.
      • Ohta K.
      • Yamamoto M.
      • Tanimoto K.
      • Fukamizu A.
      A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding.
      • Langlet F.
      • Haeusler R.A.
      • Lindén D.
      • Ericson E.
      • Norris T.
      • Johansson A.
      • Cook J.R.
      • Aizawa K.
      • Wang L.
      • Buettner C.
      • Accili D.
      Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling.
      (Figure 1). Importantly, Gck expression depends on insulin signaling via Akt, and deletion of FoxO1 partially increases Gck expression.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      In addition to FoxO1, full activation of Gck also requires activation of mTORC1
      • Wan M.
      • Leavens K.F.
      • Saleh D.
      • Easton R.M.
      • Guertin D.A.
      • Peterson T.R.
      • Kaestner K.H.
      • Sabatini D.M.
      • Birnbaum M.J.
      Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c.
      (Figure 1). It is attractive to speculate that FoxO1 inhibition of Gck could affect expression of lipogenic factors such as ChREBP, which are dependent on intracellular glucose concentrations for activation. Mechanistically, both activation of mTORC1 and inhibition of FoxO1 are required and sufficient to regulate hepatic lipogenesis in the absence of insulin signaling in vivo.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      In summary, both human and mouse data support an obligate role for hepatic insulin signaling via Akt in the regulation of hepatic lipid synthesis and fatty liver. For the remainder of this review, we focus on the molecular mechanisms mediating insulin’s control of HGP.

      Direct Regulation of HGP by Insulin

      Together with enhanced lipogenesis, insulin-resistant livers fail to suppress glycogenolysis and gluconeogenesis despite hyperinsulinemia resulting in increased HGP.
      • Lin H.V.
      • Accili D.
      Hormonal regulation of hepatic glucose production in health and disease.
      • Rizza R.A.
      Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy.
      Activation of Akt by insulin inhibits both glycogenolysis and gluconeogenesis through multiple downstream pathways including glycogen synthase kinase 3 (GSK3) and FoxO1. The canonical model of insulin suppression of glycogen synthesis is Akt-mediated phosphorylation and inhibition of GSK3
      • Cross D.A.
      • Alessi D.R.
      • Cohen P.
      • Andjelkovich M.
      • Hemmings B.A.
      Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
      (Figure 1). However, recent studies in mice with a mutant form of GSK3 that cannot be phosphorylated and inhibited by Akt, still induce glycogen synthesis in response to insulin, indicating that Akt can suppress glycogenolysis through pathways separate from Akt-dependent GSK3 phosphorylation.
      • Wan M.
      • Leavens K.F.
      • Hunter R.W.
      • Shlomit Koren
      • Von Wilamowitz-Moellendorff A.
      • Lu M.
      • Satapati S.
      • Chu Q.
      • Sakamoto K.
      • Burgess S.C.
      • Birnbaum M.J.
      A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition.
      One such independent pathway involves direct activation of glycogen synthase (GYS2). GYS2 is considered a downstream target of GSK3, however, studies have indicated that glucose-6-phosphate also directly can activate GYS2
      • Von Wilamowitz-Moellendorff A.
      • Hunter R.W.
      • García-Rocha M.
      • Kang L.
      • López-Soldado I.
      • Lantier L.
      • Patel K.
      • Peggie M.W.
      • Martínez-Pons C.
      • Voss M.
      • Calbó J.
      • Cohen P.T.W.
      • Wasserman D.H.
      • Guinovart J.J.
      • Sakamoto K.
      Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.
      (Figure 1). Because insulin signaling increases Gck expression and glucose uptake and restoration of Gck expression in the absence of Akt is sufficient to restore glycogen content,
      • Titchenell P.M.
      • Chu Q.
      • Monks B.R.
      • Birnbaum M.J.
      Hepatic insulin signaling is dispensible for suppression of glucose output by insulin in vivo.
      • Wan M.
      • Leavens K.F.
      • Hunter R.W.
      • Shlomit Koren
      • Von Wilamowitz-Moellendorff A.
      • Lu M.
      • Satapati S.
      • Chu Q.
      • Sakamoto K.
      • Burgess S.C.
      • Birnbaum M.J.
      A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition.
      • Moore M.C.
      • Coate K.C.
      • Winnick J.J.
      • An Z.
      • Cherrington A.D.
      Regulation of hepatic glucose uptake and storage in vivo.
      insulin signaling via Akt to Gck may represent a GSK3 phosphorylation-independent mechanism for glycogen synthesis.
      Classic studies in vivo and in the perfused liver have shown that insulin’s direct action on glucose regulation suppresses HGP in a fashion dependent on Akt.
      • Wan M.
      • Leavens K.F.
      • Hunter R.W.
      • Shlomit Koren
      • Von Wilamowitz-Moellendorff A.
      • Lu M.
      • Satapati S.
      • Chu Q.
      • Sakamoto K.
      • Burgess S.C.
      • Birnbaum M.J.
      A noncanonical, GSK3-independent pathway controls postprandial hepatic glycogen deposition.
      • Cherrington A.D.
      • Edgerton D.
      • Sindelar D.K.
      The direct and indirect effects of insulin on hepatic glucose production in vivo.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Cherrington A.D.
      • Moore M.C.
      • Sindelar D.K.
      • Edgerton D.S.
      Insulin action on the liver in vivo.
      Along with its roles in inhibiting lipogenesis, FoxO1 also regulates HGP downstream of Akt. FoxO1 promotes gluconeogenesis by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.
      • Lin H.V.
      • Accili D.
      Hormonal regulation of hepatic glucose production in health and disease.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      • Altomonte J.
      • Richter A.
      • Harbaran S.
      • Suriawinata J.
      • Nakae J.
      • Thung S.N.
      • Meseck M.
      • Accili D.
      • Dong H.
      Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice.
      Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.
      • Matsumoto M.
      • Pocai A.
      • Rossetti L.
      • DePinho R.A.
      • Accili D.
      Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.
      Surprisingly, deletion of FoxO1 in IR, IRS, and Akt knockout mice is sufficient to restore insulin’s suppressive effects on HGP in vivo despite a lack of autonomous insulin action.
      • Titchenell P.M.
      • Chu Q.
      • Monks B.R.
      • Birnbaum M.J.
      Hepatic insulin signaling is dispensible for suppression of glucose output by insulin in vivo.
      • Dong X.C.
      • Copps K.D.
      • Guo S.
      • Li Y.
      • Kollipara R.
      • DePinho R.A.
      • White M.F.
      Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
      • Lu M.
      • Wan M.
      • Leavens K.F.
      • Chu Q.
      • Monks B.R.
      • Ahima R.S.
      • Ueki K.
      • Kahn C.R.
      • Birnbaum M.J.
      Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      • Zhang W.
      • Patil S.
      • Chauhan B.
      • Guo C.
      • Powell D.R.
      • Le J.
      • Klotsas A.
      • Matika R.
      • Xiao X.
      • Franks R.
      • Heidenreich K.A.
      • Sajan M.P.
      • Farese R.V.
      • Stolz D.B.
      • Tso P.
      • Koo S.H.
      • Montminy M.
      • Unterman T.G.
      FoxO1 regulates multiple metabolic pathways in the liver effects on gluconeogenic, glycolytic, and lipogenic gene expression.
      • Titchenell P.M.
      • Lazar M.A.
      • Birnbaum M.J.
      Unraveling the regulation of hepatic metabolism by insulin.
      These data provide genetic evidence that supports classic physiological studies by Cherrington and Bergman
      • Mittelman S.D.
      • Fu Y.Y.
      • Rebrin K.
      • Steil G.M.
      • Bergman R.N.
      Indirect effect of insulin to suppress endogeneous glucose production is dominant, even with hyperglucoagonemia.
      • Rebrin K.
      • Steil G.M.
      • Getty L.
      • Bergman R.N.
      Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin.
      • Sindelar D.K.
      • Chu C.A.
      • Rohlie M.
      • Neal D.W.
      • Swift L.L.
      • Cherrington A.D.
      The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog.
      that extrahepatic mechanisms contribute to the regulation of HGP in vivo. Together with the obligate role of hepatic insulin action for lipid metabolism, these data challenge the classic model of selective insulin resistance in the liver and instead implicate the role of extrahepatic mechanisms in the control of HGP by insulin.

      Insulin’s Indirect Regulation of HGP

      The central nervous system plays an integral role in glucose and lipid homeostasis.
      • Myers M.G.
      • Olson D.P.
      Central nervous system control of metabolism.
      Nutrients, metabolites, and hormones signal in various regions of the hypothalamus to control metabolism. Insulin can act on neurons in the hypothalamus, particularly agouti-related peptide– and proopiomelanocortin-expressing neurons.
      • Belgardt B.F.
      • Okamura T.
      • Brüning J.C.
      Hormone and glucose signalling in POMC and AgRP neurons.
      Knockout of the insulin receptor in agouti-related peptide–expressing neurons results in a failure of insulin to inhibit HGP but had no impact on insulin’s effects on body weight.
      • Könner A.C.
      • Janoschek R.
      • Plum L.
      • Jordan S.D.
      • Rother E.
      • Ma X.
      • Xu C.
      • Enriori P.
      • Hampel B.
      • Barsh G.S.
      • Kahn C.R.
      • Cowley M.A.
      • Ashcroft F.M.
      • Brüning J.C.
      Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production.
      In response to insulin, activation of potassium adenosine triphosphate channels in the hypothalamus signals through the vagus nerve to the liver, which inhibit hepatic gluconeogenesis.
      • Pocai A.
      • Lam T.K.T.
      • Gutierrez-Juarez R.
      • Obici S.
      • Schwartz G.J.
      • Bryan J.
      • Aguilar-Bryan L.
      • Rossetti L.
      Hypothalamic KATP channels control hepatic glucose production.
      Studies from several labs, including the Rosetti Lab,
      • Inoue H.
      • Ogawa W.
      • Asakawa A.
      • Okamoto Y.
      • Nishizawa A.
      • Matsumoto M.
      • Teshigawara K.
      • Matsuki Y.
      • Watanabe E.
      • Hiramatsu R.
      • Notohara K.
      • Katayose K.
      • Okamura H.
      • Kahn C.R.
      • Noda T.
      • Takeda K.
      • Akira S.
      • Inui A.
      • Kasuga M.
      Role of hepatic STAT3 in brain-insulin action on hepatic glucose production.
      • Obici S.
      • Zhang B.B.
      • Karkanias G.
      • Rossetti L.
      Hypothalamic insulin signaling is required for inhibition of glucose production.
      have identified a brain–liver axis involving signal transducer and activator of transcription 3 signaling in hepatocytes (Figure 2). However, denervation of the hepatic branch of the vagus nerve fails to prevent insulin’s ability to suppress HGP in mice during a peripheral infusion of insulin under euglycemic clamp conditions.
      • Lam T.K.T.
      • Pocai A.
      • Gutierrez-Juarez R.
      • Obici S.
      • Bryan J.
      • Aguilar-Bryan L.
      • Schwartz G.J.
      • Rossetti L.
      Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.
      In addition, mice lacking hepatic Akt and FoxO1 suppress glucose production during hyperinsulinemic–euglycemic clamp conditions after a hepatic vagotomy, questioning the role of the brain–liver axis in the regulation of HGP.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      Moreover, recent studies in dogs have shown that blocking brain insulin signaling does not have any effect on insulin’s inhibition of HGP during clamp conditions.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      Figure thumbnail gr2
      Figure 2Indirect insulin effects on the liver. Insulin can block gluconeogenesis and glycogenolysis in the liver through several indirect pathways. Its secretion from the pancreatic β cells inhibits glucagon secretion in neighboring α cells. In the adipose tissue, insulin inhibits lipolysis, which reduces the levels of circulating FFAs, which promote glucose production. Finally, insulin signaling in the hypothalamus and central nervous system acts on Agrp neurons to signal through the hepatic vagus branch to inhibit HGP.
      Glucagon is the principal counter-regulatory hormone that stimulates glycogenolysis and gluconeogenesis during fasting and opposes the hepatic actions of insulin.
      • Altarejos J.Y.
      • Montminy M.
      CREB and the CRTC co-activators: sensors for hormonal and metabolic signals.
      Glucagon increases HGP by acutely stimulating glycogenolysis and chronically promoting gluconeogenesis
      • Lin H.V.
      • Accili D.
      Hormonal regulation of hepatic glucose production in health and disease.
      • O’Brien R.M.
      • Granner D.K.
      Regulation of gene expression by insulin.
      • Cherrington A.D.
      Control of glucose uptake and release by the liver in vivo.
      (Figure 2). Under euglycemic clamp conditions, increased insulin concentrations led to a reduction in glucagon secretion.
      • Myers S.R.
      • Diamond M.P.
      • Adkins-Marshall B.A.
      • Williams P.E.
      • Stinsen R.
      • Cherrington A.D.
      Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp.
      Moreover, human studies have indicated a close correlation of insulin action and decreased glucagon concentrations, implying some effect of insulin on glucagon secretion.
      • Sharma A.
      • Varghese R.T.
      • Shah M.
      • Man C.D.
      • Cobelli C.
      • Rizza R.A.
      • Bailey K.R.
      • Vella A.
      Impaired insulin action is associated with increased glucagon concentrations in nondiabetic humans.
      Genetic evidence also supports this correlation, indicating that deletion of the insulin receptor from α cells in mouse pancreas leads to enhanced glucagon secretion, leading to mild glucose intolerance, hyperglycemia, and hyperglucagonemia.
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      Insulin signaling in alpha cells modulates glucagon secretion in vivo.
      Because of hyperglucagonemia’s long association with diabetes, many commercial antidiabetic drugs target some part of the glucagon signaling mechanism with some success.
      • Lefèbvre P.J.
      • Paquot N.
      • Scheen A.J.
      Inhibiting or antagonizing glucagon: making progress in diabetes care.
      Despite this well-established effect on glycemia, increasing glucagon levels acutely or blocking hepatic glucagon action fails to negate insulin’s ability to suppress glucose production, indicating that insulin’s actions on suppressing glucagon are not required to acutely inhibit HGP.
      • Titchenell P.M.
      • Quinn W.J.
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      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
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      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Mittelman S.D.
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      Indirect effect of insulin to suppress endogeneous glucose production is dominant, even with hyperglucoagonemia.
      Insulin acts on adipose tissue to increase glucose uptake, suppress lipolysis, and drive lipid synthesis. As a result, insulin suppresses circulating levels of FFAs and glycerol, which correlates with changes in HGP
      • Rebrin K.
      • Steil G.M.
      • Getty L.
      • Bergman R.N.
      Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin.
      (Figure 2). Work in the canine model has shown that insulin inhibition of lipolysis contributes to the acute inhibition of hepatic glucose production.
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      • Swift L.L.
      • Cherrington A.D.
      The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog.
      Increased gluconeogenic flux largely contributes to this effect on HGP.
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      • Cherrington A.D.
      Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs.
      Recent genetic studies from several groups have supported these classic physiology studies and assert that FFA action on the liver drives HGP in insulin-resistant livers or livers completely devoid of hepatic insulin signaling.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
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      • Monks B.R.
      • Chen J.
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      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
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      • Kraft G.
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      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Perry R.J.
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      • Yang X.
      • Caprio S.
      • Susan M.
      • Sul H.S.
      • Birnbaum M.J.
      • Davis R.J.
      • Cline G.W.
      • Falk K.
      • Shulman G.I.
      Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
      Perry et al
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      • Titchenell P.M.
      • Zhang D.
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      • Davis R.J.
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      • Falk K.
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      Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
      proposed that insulin’s indirect action on the liver negates the requirement for direct hepatic insulin signaling in the control of HGP. However, other work has shown that insulin’s direct action on the liver dominates.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
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      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      Differences in experimental clamp conditions could underlie these contrasting results on the role of FFAs in the control of HGP. The experiments of Perry et al
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      • Zhang D.
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      • Caprio S.
      • Susan M.
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      • Birnbaum M.J.
      • Davis R.J.
      • Cline G.W.
      • Falk K.
      • Shulman G.I.
      Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
      involved overnight fasting mice, which left their glycogen stores depleted and made them dependent on gluconeogenesis,
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      skewing the impact of insulin’s direct action on glycogenolysis.
      • Edgerton D.S.
      • Kraft G.
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      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Titchenell P.M.
      • Lazar M.A.
      • Birnbaum M.J.
      Unraveling the regulation of hepatic metabolism by insulin.
      In addition, Perry et al
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      • Camporez J.G.
      • Kursawe R.
      • Titchenell P.M.
      • Zhang D.
      • Perry C.J.
      • Jurczak M.J.
      • Abudukadier A.
      • Han S.
      • Zhang X.M.
      • Ruan H.B.
      • Yang X.
      • Caprio S.
      • Susan M.
      • Sul H.S.
      • Birnbaum M.J.
      • Davis R.J.
      • Cline G.W.
      • Falk K.
      • Shulman G.I.
      Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
      used acetate to mimic the effects of FFAs on HGP, which blocked insulin’s ability to suppress HGP. Other groups, including the Shulman laboratory, have used the physiological substrate FFAs to directly test the contribution of adipocyte lipolysis to HGP and found insulin can suppress HGP despite increased FFAs, confirming a dominant role for hepatic insulin action in the control of HGP.
      • Titchenell P.M.
      • Quinn W.J.
      • Lu M.
      • Chu Q.
      • Lu W.
      • Li C.
      • Chen H.
      • Monks B.R.
      • Chen J.
      • Rabinowitz J.D.
      • Birnbaum M.J.
      Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Kim J.K.
      • Kim Y.J.
      • Fillmore J.J.
      • Chen Y.
      • Moore I.
      • Lee J.
      • Yuan M.
      • Li Z.W.
      • Karin M.
      • Perret P.
      • Shoelson S.E.
      • Shulman G.I.
      Prevention of fat-induced insulin resistance by salicylate.
      Moreover, studies comparing the effects of peripheral vs portal insulin infusion show significant differences in hepatic insulin levels.
      • Edgerton D.S.
      • Lautz M.
      • Scott M.
      • Everett C.A.
      • Stettler K.M.
      • Neal D.W.
      • Chu C.A.
      • Cherrington A.D.
      Insulin’ s direct effects on the liver dominate the control of hepatic glucose production.
      Peripheral insulin infusion is commonly performed during hyperinsulinemic–euglycemic clamp conditions in mice, but fails to recapitulate the proper portal insulin concentrations and may lead to an underinsulinized liver, minimizing the direct effect of insulin on HGP.
      • Edgerton D.S.
      • Kraft G.
      • Smith M.
      • Farmer B.
      • Williams P.E.
      • Coate K.C.
      • Printz R.L.
      • O'Brien R.M.
      • Cherrington A.D.
      Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.
      • Edgerton D.S.
      • Lautz M.
      • Scott M.
      • Everett C.A.
      • Stettler K.M.
      • Neal D.W.
      • Chu C.A.
      • Cherrington A.D.
      Insulin’ s direct effects on the liver dominate the control of hepatic glucose production.
      At the same time, increased insulin levels at the periphery exaggerates insulin’s indirect effects. Accounting for these factors in the clamp conditions shows that the direct effects of insulin on the liver prevail.
      • Cherrington A.D.
      • Moore M.C.
      • Sindelar D.K.
      • Edgerton D.S.
      Insulin action on the liver in vivo.
      Despite these experimental differences, an agreement has emerged that FFAs from the adipose tissue play essential roles in modulating HGP during the progression of insulin resistance and metabolic disease.
      Extensive studies have outlined the major processes of direct insulin action on the liver via the PI3K/Akt pathway and its various methods of regulating glucose and lipid homeostasis. With this knowledge, investigators have put forth a massive effort to elucidate the mechanism of hepatic insulin resistance associated with conditions such as obesity and T2DM. An attractive hypothesis in the field suggests that hepatic insulin action is selective, suggesting a bifurcation occurs distal to Akt to control lipogenesis and HGP via distinct and independent pathways. However, directly testing this model using mouse models fails to explain the pathophysiology of the insulin-resistant liver. It is becoming increasingly clear that insulin’s direct action on the liver is the driving force of hepatic de novo lipogenesis and that both direct and indirect mechanisms exist to control insulin’s regulation of hepatic glucose production. Going forward, unraveling the mechanisms of how these extrahepatic factors communicate to and regulate the liver and its ability to promote HGP in the face of increased hyperinsulinemia and subsequent lipogenesis will be paramount to fully disentangling the paradox of hepatic insulin resistance during metabolic disease.

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