A Noncanonical, GSK3-Independent Pathway Controls Postprandial Hepatic Glycogen Deposition

Wan, Min; Leavens, Karla F.; Hunter, Roger W.; Koren, Shlomit; Wilamowitz-Moellendorff, Alexander von; Lu, Mingjian; Satapati, Santhosh; Chu, Qingwei; Sakamoto, Kei; Burgess, Shawn C.; Birnbaum, Morris J.

doi:10.1016/j.cmet.2013.06.001

Cited by 70 publications

(76 citation statements)

References 27 publications

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“…Hepatic insulin resistance in mice lacking both hepatic Akt1 and Akt2 (double liver KO; DLKO) was essentially normalized by the additional deletion of FOXO1, in a triple KO (TLKO) mouse model (11). Remarkably, the TLKO mice exhibited relatively normal fasting and postprandial glucose tolerance (10). This suggests that FOXO1 deletion enables other mechanisms to normalize hepatic glucose metabolism.…”

Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 78%

“…Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation of glycogen synthesis (10). Hepatic insulin resistance in mice lacking both hepatic Akt1 and Akt2 (double liver KO; DLKO) was essentially normalized by the additional deletion of FOXO1, in a triple KO (TLKO) mouse model (11).…”

Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 99%

“…The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux Varman T. Samuel 1,2 and Gerald I. Shulman phosphorylation of GSK3 appears dispensable for normal hepatic glucose metabolism (10). Thus, Akt activation is not a linchpin for coordinating hepatic glucose metabolism, and other pathways also regulate this process.…”

Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 99%

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The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,010

819

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In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

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Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 78%

Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 99%

Section: Postprandial Hepatic Glucose and Lipid Metabolismmentioning

confidence: 99%

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The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Samuel¹,

Shulman²

2016

Journal of Clinical Investigation

1,010

819

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“…The period between meals is called the postprandial state. Postprandial mouse models are widely accepted to study in vivo hepatic mTORC1 signaling (1)(2)(3)(4); in this tissue, mTORC1 is active when the ribosomal protein S6 is phosphorylated at residues Ser240/244 (hereby referred as phospho-S6) and is inactive when these two amino acids are not phosphorylated (3). For this study, we developed a postprandial protocol (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The liver is a key organ responsible for nutrient sensing and the maintenance of wholebody energy homeostasis. Therefore, we considered the liver as a primary model to examine the changes in mitochondrial plasticity that accompanies physiological transitions in feeding and postprandial metabolism (1)(2)(3)(4).…”

mentioning

confidence: 99%

A Mitofusin-2–dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

Sood

Jeyaraju

Prudent

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

156

178

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Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.T he last decade expanded our understanding of the importance of mitochondrial shape, position, and interorganellar interactions in the regulation of cell stress. For example, mitochondrial hyperfusion is a stress response that protects against cell death and autophagic degradation, whereas chronic stress triggers mitochondrial fragmentation and cell death. However, the in vivo implications of mitochondrial plasticity under normal physiological conditions are still largely unknown. The liver is a key organ responsible for nutrient sensing and the maintenance of wholebody energy homeostasis. Therefore, we considered the liver as a primary model to examine the changes in mitochondrial plasticity that accompanies physiological transitions in feeding and postprandial metabolism (1-4).The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase that plays an important role in regulating metabolism and cell growth in response to anabolic signals (5). Studies indicate that mTORC1, which is activated by growth factors and amino acids, is a key sensor allowing cells and tissues to adapt their metabolism in response to the nutritional state (5). In the liver, it controls the activation of various metabolic proce...

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Regulation of glucose metabolism in liver

Burgess

2015

International Textbook of Diabetes Mellitus

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A Noncanonical, GSK3-Independent Pathway Controls Postprandial Hepatic Glycogen Deposition

Cited by 70 publications

References 27 publications

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

A Mitofusin-2–dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

Regulation of glucose metabolism in liver

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