Cell Metabolism
This journal offers authors two options (open access or subscription) to publish research

May 02, 2012

Volume 15Issue 5p563-788
Open Archive
On the cover: There are a number of hypotheses as to how excess nutrients cause insulin resistance, diabetes, and fatty liver disease. For this Special Focus on Lipids and Insulin Resistance, Cell Metabolism is pleased to present ten Perspectives, each putting forward one of the leading hypotheses underlying the mechanism(s) connecting nutrients and insulin resistance. The cover, designed by Yvonne Blanco, is an artistic rendition of the “maze-like” effect where many paths may lead to insulin resistance and fatty liver disease....
On the cover: There are a number of hypotheses as to how excess nutrients cause insulin resistance, diabetes, and fatty liver disease. For this Special Focus on Lipids and Insulin Resistance, Cell Metabolism is pleased to present ten Perspectives, each putting forward one of the leading hypotheses underlying the mechanism(s) connecting nutrients and insulin resistance. The cover, designed by Yvonne Blanco, is an artistic rendition of the “maze-like” effect where many paths may lead to insulin resistance and fatty liver disease.


  • Cell Metabolism 2012 Focus on Lipids and Insulin Resistance

    • Nikla Emambokus,
    • Anne Granger
    Insulin resistance and diabetes are often linked to excess lipid accumulation, and a number of different hypotheses for the underlying mechanism linking lipids and insulin resistance have been put forward. It is a matter for discussion whether it is a “chicken and egg” situation or, if at all, an obligatory connection. In this issue, a “Special Focus on Lipids and Insulin Resistance,” we present ten Perspectives, each discussing a specific aspect of the connection between nutrients and lipid resistance and their relationships to nonalcoholic fatty liver disease.

In Translation

  • Omega 3 Fatty Acids and GPR120

    • Da Young Oh,
    • Jerrold M. Olefsky
    Human loss-of-function gene variants in GPR120 have recently been identified that confer increased risk for obesity and metabolic syndrome. In addition, GPR120 KO mice develop obesity, increased inflammation, and insulin resistance, consistent with a role for GPR120 signaling in the metabolic syndrome and diabetes mellitus.


  • Fortifying the Link between SIRT1, Resveratrol, and Mitochondrial Function

    • John M. Denu
    The molecular mechanisms behind the health benefits of resveratrol remain enigmatic and controversial. In this issue of Cell Metabolism, Price et al. establish a clear chemical-genetic connection between SIRT1 and resveratrol, providing strong evidence that SIRT1 is critical for resveratrol to stimulate mitochondrial biogenesis and a switch toward oxidative muscle fibers (Price et al., 2012).
  • Muscling In on PGC-1α for Improved Quality of Life in ALS

    • Ashu Johri,
    • M. Flint Beal
    Impaired activity of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α has been implicated in the pathophysiology of several neurodegenerative disorders. In this issue, Da Cruz et al. (2012) show improved muscle function, but not survival, with increased PGC-1α activity in muscle in a mouse model of amyotrophic lateral sclerosis.


  • The Problem of Establishing Relationships between Hepatic Steatosis and Hepatic Insulin Resistance

    • Robert V. Farese Jr.,
    • Rudolf Zechner,
    • Christopher B. Newgard,
    • Tobias C. Walther
    Excessive deposition of fat in the liver (hepatic steatosis) is frequently accompanied by hepatic insulin resistance. Whether this correlation is due to a causal relationship between the conditions has been the subject of considerable debate, and the literature abounds with conflicting data and theories. Here we provide a perspective by defining the problem and its challenges, analyzing the possible causative relationships, and drawing some conclusions.
  • Diacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance

    • François R. Jornayvaz,
    • Gerald I. Shulman
    Nonalcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in Western societies, affecting one in four adults in the USA, and is strongly associated with hepatic insulin resistance, a major risk factor in the pathogenesis of type 2 diabetes. Although the cellular mechanisms underlying this relationship are unknown, hepatic accumulation of diacylglycerol (DAG) in both animals and humans has been linked to hepatic insulin resistance. In this Perspective, we discuss the role of DAG activation of protein kinase Cε as the mechanism responsible for NAFLD-associated hepatic insulin resistance seen in obesity, type 2 diabetes, and lipodystrophy.
  • A Ceramide-Centric View of Insulin Resistance

    • Jose A. Chavez,
    • Scott A. Summers
    The recent implementation of genomic and lipidomic approaches has produced a large body of evidence implicating the sphingolipid ceramide in a diverse range of physiological processes and as a critical modulator of cellular stress. In this review, we discuss from a historical perspective the most important discoveries produced over the last decade supporting a role for ceramide and its metabolites in the pathogenesis of insulin resistance and other obesity-associated metabolic diseases. Moreover, we describe how a ceramide-centric view of insulin resistance might be reconciled in the context of other prominent models of nutrient-induced insulin resistance.
  • Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle

    • Deborah M. Muoio,
    • P. Darrell Neufer
    The interplay between mitochondrial energetics, lipid balance, and muscle insulin sensitivity has remained a topic of intense interest and debate for decades. One popular view suggests that increased oxidative capacity benefits metabolic wellness, based on the premise that it is healthier to burn fat than glucose. Attempts to test this hypothesis using genetically modified mouse models have produced contradictory results and instead link muscle insulin resistance to excessive fat oxidation, acylcarnitine production, and increased mitochondrial H2O2-emitting potential.
  • Interplay between Lipids and Branched-Chain Amino Acids in Development of Insulin Resistance

    • Christopher B. Newgard
    Fatty acids (FA) and FA-derived metabolites have long been implicated in the development of insulin resistance and type 2 diabetes. Surprisingly, application of metabolomics technologies has revealed that branched-chain amino acids (BCAA) and related metabolites are more strongly associated with insulin resistance than many common lipid species. Moreover, the BCAA-related signature is predictive of incident diabetes and intervention outcomes and uniquely responsive to therapeutic interventions. Nevertheless, in animal feeding studies, BCAA supplementation requires the background of a high-fat diet to promote insulin resistance.
  • Nuclear Receptors Reverse McGarry's Vicious Cycle to Insulin Resistance

    • David D. Moore
    Several pathways and pathologies have been suggested as connections between obesity and diabetes, including inflammation of adipose and other tissues, toxic lipids, endoplasmic reticulum stress, and fatty liver. One specific proposal is that insulin resistance induces a vicious cycle in which hyperinsulinemia increases hepatic lipogenesis and exacerbates fatty liver, in turn further increasing insulin resistance. Here I suggest that reversing this cycle via suppression of the lipogenic transcription factor SREBP-1c is a common thread that connects the antidiabetic effects of a surprising number of nuclear hormone receptors, including CAR, LRH-1, TRβ, ERα, and FXR/SHP.
  • The Role of Endoplasmic Reticulum in Hepatic Lipid Homeostasis and Stress Signaling

    • Suneng Fu,
    • Steven M. Watkins,
    • Gökhan S. Hotamisligil
    The endoplasmic reticulum (ER) is a critical site of protein, lipid, and glucose metabolism, lipoprotein secretion, and calcium homeostasis. Many of the sensing, metabolizing, and signaling mechanisms for these pathways exist within or on the ER membrane domain. Here, we review the cellular functions of ER, how perturbation of ER homeostasis contributes to metabolic dysregulation and potential causative mechanisms of ER stress in obesity, with a particular focus on lipids, metabolic adaptations of ER, and the maintenance of its membrane homeostasis.
  • Inflammation and Lipid Signaling in the Etiology of Insulin Resistance

    • Christopher K. Glass,
    • Jerrold M. Olefsky
    Inflammation and lipid signaling are intertwined modulators of homeostasis and immunity. In addition to the extensively studied eicosanoids and inositol phospholipids, emerging studies indicate that many other lipid species act to positively and negatively regulate inflammatory responses. Conversely, inflammatory signaling can significantly alter lipid metabolism in the liver, adipose tissue, skeletal muscle, and macrophage in the context of infection, diabetes, and atherosclerosis. Here, we review recent findings related to this interconnected network from the perspective of immunity and metabolic disease.
  • Lipid Sensing and Insulin Resistance in the Brain

    • Jessica T.Y. Yue,
    • Tony K.T. Lam
    Lipid sensing and insulin signaling in the brain independently triggers a negative feedback system to lower glucose production and food intake. Here, we discuss the underlying molecular and neuronal mechanisms of lipid sensing and insulin signaling in the hypothalamus and how these mechanisms are affected in response to high-fat feeding. We propose that high-fat feeding concurrently disrupts hypothalamic insulin-signaling and lipid-sensing mechanisms and that experiments aimed to restore both insulin action and lipid sensing in the brain could effectively lower glucose production and food intake to restore metabolic homeostasis in type 2 diabetes and obesity.
  • Evidence against a Physiologic Role for Acute Changes in CNS Insulin Action in the Rapid Regulation of Hepatic Glucose Production

    • Christopher J. Ramnanan,
    • Dale S. Edgerton,
    • Alan D. Cherrington
    This Perspective will discuss the physiologic relevance of data that suggest CNS insulin action is required for the rapid suppression of hepatic glucose production. It will also review data from experiments on the conscious dog, which show that although the canine brain can sense insulin and, thereby, regulate hepatic glucoregulatory enzyme expression, CNS insulin action is not essential for the rapid suppression of glucose production caused by the hormone. Insulin's direct hepatic effects are dominant, thus it appears that insulin's central effects are redundant in the acute regulation of hepatic glucose metabolism.


  • Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease

    • Hae-Ki Min,
    • Ashwani Kapoor,
    • Michael Fuchs,
    • Faridoddin Mirshahi,
    • Huiping Zhou,
    • James Maher,
    • John Kellum,
    • Russell Warnick,
    • Melissa J. Contos,
    • Arun J. Sanyal
    Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR.
  • SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function

    • Nathan L. Price,
    • Ana P. Gomes,
    • Alvin J.Y. Ling,
    • Filipe V. Duarte,
    • Alejandro Martin-Montalvo,
    • Brian J. North,
    • Beamon Agarwal,
    • Lan Ye,
    • Giorgio Ramadori,
    • Joao S. Teodoro,
    • Basil P. Hubbard,
    • Ana T. Varela,
    • James G. Davis,
    • Behzad Varamini,
    • Angela Hafner,
    • Ruin Moaddel,
    • Anabela P. Rolo,
    • Roberto Coppari,
    • Carlos M. Palmeira,
    • Rafael de Cabo,
    • Joseph A. Baur,
    • David A. Sinclair
    Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD+ levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits.
  • Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase

    • Manju Kumari,
    • Gabriele Schoiswohl,
    • Chandramohan Chitraju,
    • Margret Paar,
    • Irina Cornaciu,
    • Ashraf Y. Rangrez,
    • Nuttaporn Wongsiriroj,
    • Harald M. Nagy,
    • Pavlina T. Ivanova,
    • Sarah A. Scott,
    • Oskar Knittelfelder,
    • Gerald N. Rechberger,
    • Ruth Birner-Gruenberger,
    • Sandra Eder,
    • H. Alex Brown,
    • Guenter Haemmerle,
    • Monika Oberer,
    • Achim Lass,
    • Erin E. Kershaw,
    • Robert Zimmermann,
    • Rudolf Zechner
    Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs.
  • IRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action

    • Marianna Sadagurski,
    • Rebecca L. Leshan,
    • Christa Patterson,
    • Aldo Rozzo,
    • Alexandra Kuznetsova,
    • Josh Skorupski,
    • Justin C. Jones,
    • Ronald A. Depinho,
    • Martin G. Myers Jr.,
    • Morris F. White
    Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Leprcre together with Irs2L/L to ablate Irs2 expression in LepR-b neurons (LeprΔIrs2). LeprΔIrs2 mice developed obesity, glucose intolerance, and insulin resistance.
  • TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO

    • Stacey Robida-Stubbs,
    • Kira Glover-Cutter,
    • Dudley W. Lamming,
    • Masaki Mizunuma,
    • Sri Devi Narasimhan,
    • Elke Neumann-Haefelin,
    • David M. Sabatini,
    • T. Keith Blackwell
    The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop.
  • Hepatic mTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c

    • Asami Hagiwara,
    • Marion Cornu,
    • Nadine Cybulski,
    • Pazit Polak,
    • Charles Betz,
    • Francesca Trapani,
    • Luigi Terracciano,
    • Markus H. Heim,
    • Markus A. Rüegg,
    • Michael N. Hall
    Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety.
  • Calcium Signaling through CaMKII Regulates Hepatic Glucose Production in Fasting and Obesity

    • Lale Ozcan,
    • Catherine C.L. Wong,
    • Gang Li,
    • Tao Xu,
    • Utpal Pajvani,
    • Sung Kyu Robin Park,
    • Anetta Wronska,
    • Bi-Xing Chen,
    • Andrew R. Marks,
    • Akiyoshi Fukamizu,
    • Johannes Backs,
    • Harold A. Singer,
    • John R. Yates III,
    • Domenico Accili,
    • Ira Tabas
    Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects.
  • Ablation of Steroid Receptor Coactivator-3 Resembles the Human CACT Metabolic Myopathy

    • Brian York,
    • Erin L. Reineke,
    • Jørn V. Sagen,
    • Bryan C. Nikolai,
    • Suoling Zhou,
    • Jean-Francois Louet,
    • Atul R. Chopra,
    • Xian Chen,
    • Graham Reed,
    • Jeffrey Noebels,
    • Adekunle M. Adesina,
    • Hui Yu,
    • Lee-Jun C. Wong,
    • Anna Tsimelzon,
    • Susan Hilsenbeck,
    • Robert D. Stevens,
    • Brett R. Wenner,
    • Olga Ilkayeva,
    • Jianming Xu,
    • Christopher B. Newgard,
    • Bert W. O'Malley
    Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression.
  • Muscle-Specific Deletion of Carnitine Acetyltransferase Compromises Glucose Tolerance and Metabolic Flexibility

    • Deborah M. Muoio,
    • Robert C. Noland,
    • Jean-Paul Kovalik,
    • Sarah E. Seiler,
    • Michael N. Davies,
    • Karen L. DeBalsi,
    • Olga R. Ilkayeva,
    • Robert D. Stevens,
    • Indu Kheterpal,
    • Jingying Zhang,
    • Jeffrey D. Covington,
    • Sudip Bajpeyi,
    • Eric Ravussin,
    • William Kraus,
    • Timothy R. Koves,
    • Randall L. Mynatt
    The concept of “metabolic inflexibility” was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance.

Short Article

  • Elevated PGC-1α Activity Sustains Mitochondrial Biogenesis and Muscle Function without Extending Survival in a Mouse Model of Inherited ALS

    • Sandrine Da Cruz,
    • Philippe A. Parone,
    • Vanda S. Lopes,
    • Concepción Lillo,
    • Melissa McAlonis-Downes,
    • Sandra K. Lee,
    • Anne P. Vetto,
    • Susanna Petrosyan,
    • Martin Marsala,
    • Anne N. Murphy,
    • David S. Williams,
    • Bruce M. Spiegelman,
    • Don W. Cleveland
    The transcriptional coactivator PGC-1α induces multiple effects on muscle, including increased mitochondrial mass and activity. Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, adult-onset neurodegenerative disorder characterized by selective loss of motor neurons and skeletal muscle degeneration. An early event is thought to be denervation-induced muscle atrophy accompanied by alterations in mitochondrial activity and morphology within muscle. We now report that elevation of PGC-1α levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1α-dependent pathways throughout disease course.