Inflammation and metabolic disorders
NaturePublished 13 December 2006
Gökhan S. Hotamışlıgil
Citations8,955
SJR quartileQ1
SJR score18.29
SNIP10.16
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
Dysfunction of the immune response and metabolic regulation interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease.
Abstract
Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
Keywords
Medicine
Nature GeneticsPGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
10,641 Citations2003Vamsi K. Mootha, Cecilia M. Lindgren +19 more
An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
NatureBiochemistry and molecular cell biology of diabetic complications
8,920 Citations2001Michael Brownlee
Journal of Clinical InvestigationObesity is associated with macrophage accumulation in adipose tissue
8,556 Citations2003Stuart P. Weisberg, Daniel McCann +4 more
Transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob) found that the expression of 1,304 transcripts correlated significantly with body mass.
Journal of Clinical InvestigationObesity is associated with macrophage accumulation in adipose tissue
8,280 Citations2003Stuart P. Weisberg, Daniel McCann +4 more
ScienceAdipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance
7,453 Citations1993Gökhan S. Hotamışlıgil, Narinder S. Shargill +1 more
A role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity is indicated.
Journal of Clinical InvestigationChronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
5,833 Citations2003Haiyan Xu, Glenn T. Barnes +9 more
It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
Journal of Clinical InvestigationChronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
5,610 Citations2003Haiyan Xu, Glenn T. Barnes +9 more
Journal of Clinical InvestigationIncreased oxidative stress in obesity and its impact on metabolic syndrome
5,278 Citations2004Shigetada Furukawa, Takuya Fujita +8 more
It is suggested that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
Journal of Clinical InvestigationInflammation and insulin resistance
4,611 Citations2006Steven E. Shoelson
The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
Journal of Clinical InvestigationInflammation, stress, and diabetes
3,886 Citations2005Kathryn E. Wellen, Gökhan S. Hotamışlıgil
The molecular and cellular underpinnings of obesity-induced inflammation and the signaling pathways at the intersection of metabolism and inflammation that contribute to diabetes are discussed.
ScienceEndoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
3,827 Citations2004Umut Özcan, Qiong Cao +8 more
It is shown that obesity causes endoplasmic reticulum (ER) stress, which leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptors substrate–1 (IRS-1).
Journal of Clinical InvestigationTLR4 links innate immunity and fatty acid–induced insulin resistance
3,621 Citations2006Hang Shi, Maia V. Kokoeva +4 more
It is suggested that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
Journal of Clinical InvestigationIncreased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
3,501 Citations1995Gökhan S. Hotamışlıgil, Peter Arner +3 more
A role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance is suggested as well as the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA.
NatureA central role for JNK in obesity and insulin resistance
3,336 Citations2002Jiro Hirosumi, Gürol Tuncman +6 more
It is shown that JNK activity is abnormally elevated in obesity and an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity.
NatureProtein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
3,312 Citations1999Heather P. Harding, Yuhong Zhang +1 more
The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
Annual Review of BiochemistryTHE MAMMALIAN UNFOLDED PROTEIN RESPONSE
3,020 Citations2005Martin Schröder, Randal J. Kaufman
ScienceCoupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1
2,964 Citations2000Fumihiko Urano, Xiao-Zhong Wang +5 more
Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs), and Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and I RE1alpha-/- fibroblasts were impaired in JNK activation by ER stress.
Nature Reviews Molecular Cell BiologyCritical nodes in signalling pathways: insights into insulin action
2,724 Citations2006Cullen M. Taniguchi, Brice Emanuelli +1 more
ScienceIRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance
2,606 Citations1996Gökhan S. Hotamışlıgil, Pascal Peraldi +4 more
Results indicate that TNF-α induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
NatureReactive oxygen species have a causal role in multiple forms of insulin resistance
2,522 Citations2006Nicholas Houstis, Evan D. Rosen +1 more
A genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-α and the other with the glucocorticoid dexamethasone, suggests that reactive oxygen species levels are increased in both models, and increased ROS levels are an important trigger for insulin resistance in numerous settings.
Journal of Lipid ResearchAdipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans
2,474 Citations2005Saverio Cinti, Grant A. Mitchell +8 more
It is demonstrated that >90% of all macrophages in WAT of obese mice and humans are localized to dead adipocytes, where they fuse to form syncytia that sequester and scavenge the residual “free” adipocyte lipid droplet and ultimately form multinucleate giant cells, a hallmark of chronic inflammation.
ScienceChemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
2,414 Citations2006Umut Özcan, Erkan Yılmaz +6 more
It is demonstrated that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.
Nature MedicineLocal and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
2,230 Citations2005Dongsheng Cai, Minsheng Yuan +5 more
It is shown that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-κB activation and downstream cytokine production, which causes insulin resistance both locally in liver and systemically.
NatureProtection from obesity-induced insulin resistance in mice lacking TNF-α function
2,230 Citations1997K. Teoman Uysal, Sarah M. Wiesbrock +2 more
Results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
CellSuppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators
2,220 Citations2006Julie St‐Pierre, Stavit Drori +11 more
Increase in PGC-1alpha levels dramatically protects neural cells in culture from oxidative-stressor-mediated death, providing a potential target for the therapeutic manipulation of these important endogenous toxins.
Trends in ImmunologyInflammation: the link between insulin resistance, obesity and diabetes
2,147 Citations2003P Dandona
The increased concentrations of TNF-alpha and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction, which might interfering with the anti-inflammatory effect of insulin, which in turn might promote inflammation.
ScienceNuclear Receptors and Lipid Physiology: Opening the X-Files
2,076 Citations2001Ajay Chawla, Joyce J. Repa +2 more
Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
ScienceMitochondrial Dysfunction and Type 2 Diabetes
2,051 Citations2005Bradford B. Lowell, Gerald I. Shulman
Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.
Molecular CellPerk Is Essential for Translational Regulation and Cell Survival during the Unfolded Protein Response
2,008 Citations2000Heather P. Harding, Yuhong Zhang +3 more
ScienceReversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of <i>Ikkβ</i>
1,867 Citations2001Minsheng Yuan, Nicky Konstantopoulos +5 more
It is shown that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling and identifies the IKKβ pathway as a target for insulin sensitization.
Nature MedicineIKK-β links inflammation to obesity-induced insulin resistance
1,755 Citations2005Melek C. Arkan, Andrea L. Hevener +8 more
IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance, demonstrating the importance of liver cell IKK- beta in hepatic insulin resistance and the central role of myeloids cells in development of systemic insulin resistance.
Journal of Alzheimer s DiseaseImpaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?
1,679 Citations2005Eric van Steen, Benjamin M. Terry +7 more
The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system neurons, the expression levels are markedly reduced in AD.
Trends in Cell BiologySignal transduction by tumor necrosis factor and its relatives
1,644 Citations2001Véronique Baud, Michael Karin
This review focuses on proteins that transduce the signals generated at TNF receptors to nuclear targets such as AP-1 and NF-kappaB, which are likely to be used by other members of the TNF family.
Journal of Biological ChemistryMechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle
1,547 Citations2002Chunli Yu, Yan Chen +12 more
The hypothesis that an increase in plasma fatty acid concentration results in a increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-θ leading to increased IRS-1 Ser307 phosphorylation is supported.
Journal of Biological ChemistryThe c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307
1,471 Citations2000Vincent Aguirre, Tohru Uchida +3 more
Results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.
Journal of Clinical InvestigationThe expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase.
1,298 Citations1995Philip A. Kern, Mehrnoosh Saghizadeh +4 more
The data suggest that endogenous TNF expression in adipose tissue may help limit obesity in some subjects, perhaps by increasing insulin resistance and decreasing LPL.
DiabetesFree fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
1,257 Citations1999Michael Griffin, M. Marcucci +8 more
It is concluded that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity.
Molecular ImmunologyInnate immunity: an overview
1,252 Citations2003Bruce Beutler
The effector arm of innate immunity has been tackled, largely though the use of biochemical methods, and genetic dissection of innate immune pathways has been pursued with great success in model organisms.
Journal of Biological ChemistryPPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth
1,158 Citations2001Evan D. Rosen, Bruce M. Spiegelman
This review will focus on PPAR, an important subfamily of the nuclear hormone receptor (NHR) superfamily that has been intensively studied for more than a decade and implicated in such diverse pathways as lipid and glucose homeostasis, control of cellular proliferation, and differentiation.
Nature MedicineReciprocal regulation of inflammation and lipid metabolism by liver X receptors
1,139 Citations2003Sean B. Joseph, Antonio Castrillo +3 more
It is demonstrated that in vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice and LXR ligands inhibit the expression of inflammatory mediators in response to bacterial infection or LPS stimulation.
CellAnatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network
1,001 Citations2006Angie L. Bookout, Yangsik Jeong +4 more
These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale and distinguishes between reproduction, development, and growth and nutrient uptake, metabolism, and excretion.
Physiological ReviewsEndoplasmic Reticulum Stress Signaling in Disease
947 Citations2006Stefan J. Marciniak, David Ron
This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.
ScienceUncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in <i>aP2</i> , the Adipocyte Fatty Acid Binding Protein
924 Citations1996Gökhan S. Hotamışlıgil, Randall S. Johnson +4 more
Results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-α.
American Journal of Physiology-Endocrinology and MetabolismIRS proteins and the common path to diabetes
917 Citations2002Morris F. White
The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing.
Journal of Biological ChemistrySOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2
887 Citations2002Liangyou Rui, Minsheng Yuan +3 more
SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy.
EndocrinologyMinireview: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors
887 Citations2003Chih‐Hao Lee, Peter Olson +1 more
CellEndoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response
815 Citations2006Kezhong Zhang, Xiaohua Shen +6 more
The studies delineate a molecular mechanism for activation of an ER-localized transcription factor, CREBH, and reveal an unprecedented link by which ER stress initiates an acute inflammatory response.
Journal of Biological ChemistrySerine Phosphorylation of Insulin Receptor Substrate 1 by Inhibitor κB Kinase Complex
759 Citations2002Zhan‐Guo Gao, Daniel Hwang +5 more
It is suggested that IRS- 1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.
Molecular and Cellular BiologyAutocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression
733 Citations2006Ping Hu, Han Zhang +3 more
Investigation finds that inhibiting NF-κB significantly decreased ER stress-induced cell death in a caspase-8-dependent manner, and suggests that ER stress induces two signals, namely TNF-α induction and TRAF2 down-regulation, which work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.
Journal of Clinical InvestigationThe expression of TNF alpha by human muscle. Relationship to insulin resistance.
714 Citations1996Mehrnoosh Saghizadeh, Juling Ong +3 more
TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects, which suggest another mechanism by which TNF may play an important role in human insulin resistance.
Nature MedicineLack of macrophage fatty-acid–binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis
685 Citations2001Liza Makowski, Jeffrey B. Boord +9 more
Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.
CellMolecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors
640 Citations2005Sumito Ogawa, Jean Lozach +9 more
Signals and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages are reported and combinatorial control of homeostasis and immune responses by nuclear receptors is revealed and new approaches for treatment of inflammatory diseases are suggested.
Molecular and Cellular BiologyTranslational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2
634 Citations2004Jing Deng, Phoebe D. Lu +6 more
Pulse-chase labeling experiments indicate that repression of IκBα translation plays an important role in NF-κB activation in cells experiencing high levels of eIF2α phosphorylation, and suggest a direct role for eif2αosphorylation-dependent translational control in activating NF-kkB during ER stress.
Journal of Clinical InvestigationMechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
626 Citations2002Ripudaman S. Hundal, Kitt Falk Petersen +5 more
The hypothesis that IKKbeta represents a new target for treating type 2 diabetes mellitus is supported.
Journal of Clinical InvestigationMechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
566 Citations2002Ripudaman S. Hundal, Kitt Falk Petersen +5 more
Journal of Biological ChemistryA Molecular Basis for Insulin Resistance
548 Citations1997Keren Paz, Rina Hemi +5 more
It is suggested that insulin resistance is associated with enhanced Ser/Thr phosphorylation of IRS-1 and IRS-2, which impairs their interaction with the JM region of IR, which abolishes their ability to undergo insulin-induced Tyrosphorylation and propagate the insulin receptor signal.
ScienceFunction of GATA Transcription Factors in Preadipocyte-Adipocyte Transition
541 Citations2000Qiang Tong, Gökhan Dalgin +4 more
It is shown that murine GATA-2 and Gata-3 are specifically expressed in white adipocyte precursors and that their down-regulation sets the stage for terminal differentiation.
The International Journal of Biochemistry & Cell BiologyCoordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway
538 Citations2005Sara B. Cullinan, J. Alan Diehl
Progress is discussed regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways are discussed.
DiabetesFree Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-κB Pathway in Rat Liver
526 Citations2005Guenther Boden, Pengxiang She +7 more
It is concluded that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis.
DiabetesEffects of an Engineered Human Anti–TNF-α Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM
512 Citations1996Francis Ofei, Steve Hurel +3 more
TNF-α neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese NIDDM subjects and C-peptide remained unaffected by the type of treatment throughout the study.
Journal of Biological ChemistryThe Hyperglycemia-induced Inflammatory Response in Adipocytes
492 Citations2004Ying Lin, Anders H. Berg +14 more
Analysis of adipocytes exposed to hyperglycemia both in vitro as well as in vivo highlights the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.
Nature MedicineEnhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3
491 Citations2004Jane K. Howard, Belinda J. Cave +4 more
It is reported here that Socs3+/− mice display greater leptin sensitivity than wild-type control mice and are significantly protected against the development of diet-induced obesity and associated metabolic complications.
Molecular CellCrosstalk between LXR and Toll-like Receptor Signaling Mediates Bacterial and Viral Antagonism of Cholesterol Metabolism
489 Citations2003Antonio Castrillo, Sean B. Joseph +5 more
It is demonstrated here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway, a common mechanism whereby bacterial and viral pathogens may modulate macrophages cholesterol metabolism and cardiovascular disease.
Developmental CellProgrammed Autophagy in the Drosophila Fat Body Is Induced by Ecdysone through Regulation of the PI3K Pathway
489 Citations2004Tor Erik Rusten, Karine Lindmo +5 more
Genetic interaction studies showed that ecdysone signaling downregulates PI3K signaling and that this represents the effector mechanism for induction of programmed autophagy, and these studies link hormonal induction ofAutophagy to the regulatory function of the PI3k signaling pathway in vivo.
Cell MetabolismAdipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes
489 Citations2005Kazuhisa Maeda, Haiming Cao +12 more
Nature reviews. ImmunologyCombinatorial roles of nuclear receptors in inflammation and immunity
477 Citations2005Christopher K. Glass, Sumito Ogawa
It is suggested that by using receptor-specific mechanisms, PPARs and LXRs function in a combinatorial manner with the glucocorticoid receptor to integrate local and systemic responses to inflammation.
Journal of Clinical InvestigationInsulin resistance and atherosclerosis
473 Citations2006Clay F. Semenkovich
It is suggested that insulin resistance and atherosclerosis could represent independent and ultimately maladaptive responses to the disruption of cellular homeostasis caused by the excess delivery of fuel.
Journal of Biological ChemistryInvolvement of Endoplasmic Reticulum Stress in Insulin Resistance and Diabetes
462 Citations2004Yoshihisa Nakatani, Hideaki Kaneto +9 more
It is shown that endoplasmic reticulum (ER) stress plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress.
Journal of Clinical InvestigationPKC-θ knockout mice are protected from fat-induced insulin resistance
454 Citations2004Jason K. Kim, Jonathan J. Fillmore +10 more
It is demonstrated that PKC-θ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggested that PKc-η is a potential therapeutic target for the treatment of type 2 diabetes.
Biochemical and Biophysical Research CommunicationsActivation of Toll-like receptor 4 is associated with insulin resistance in adipocytes
448 Citations2006Min Jeong Song, Kang Ho Kim +2 more
Results suggest that activation of TLR4 in adipocyte might be implicated in the onset of insulin resistance in obesity and type 2 diabetes.
Journal of Biological ChemistrySOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice
446 Citations2001Brice Emanuelli, Pascal Peraldi +6 more
It is shown that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase, which suggests that it is a player in the development of insulin resistance.
Recent Progress in Hormone ResearchPeroxisome Proliferator-Activated Receptors: From Genes to Physiology
425 Citations2001Steven A. Kliewer
Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
Journal of Biological ChemistryTumor Necrosis Factor α (TNFα) Induces the Unfolded Protein Response (UPR) in a Reactive Oxygen Species (ROS)-dependent Fashion, and the UPR Counteracts ROS Accumulation by TNFα
396 Citations2005Xin Xue, Jiang‐Hu Piao +8 more
It is shown that murine fibrosarcoma L929 cells, in which tumor necrosis factor (TNF) α induces accumulation of reactive oxygen species (ROS) and cell death, show that TNFα induces the UPR in a ROS-dependent fashion.
Journal of Clinical InvestigationPKC-θ knockout mice are protected from fat-induced insulin resistance
387 Citations2004Jason K. Kim, Jonathan J. Fillmore +10 more
Journal of Biological ChemistryThe Lipopolysaccharide-activated Toll-like Receptor (TLR)-4 Induces Synthesis of the Closely Related Receptor TLR-2 in Adipocytes
351 Citations2000Ying Lin, Hyangkyu Lee +4 more
The studies demonstrate the presence of a fully intact pathway of innate immunity in the adipocyte that can be activated by LPS binding to the cell surface and results in the secretion of immunomodulatory molecules.
Proceedings of the National Academy of SciencesFunctional <i>in vivo</i> interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
344 Citations2006Gürol Tuncman, Jiro Hirosumi +4 more
Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of J NK2 in isolated mutant mice.
Nature MedicinePossible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide
336 Citations2004Hideaki Kaneto, Yoshihisa Nakatani +8 more
Intraperitoneal administration of the peptide markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice, indicating that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.
Science s STKESer/Thr Phosphorylation of IRS Proteins: A Molecular Basis for Insulin Resistance
318 Citations2005Yehiel Zick
S6K1, like other serine and threonine kinases activated by insulin, has recently been shown to participate in negative feedback mechanisms aimed at terminating insulin signaling through IRS (insulin receptor substrate) phosphorylation.
Journal of NutritionFatty Acid Binding Proteins—The Evolutionary Crossroads of Inflammatory and Metabolic Responses
312 Citations2004Liza Makowski, Gökhan S. Hotamışlıgil
This review will focus on how FABPs direct lipid traffic and simultaneously control inflammatory and metabolic pathways under the pressures of the Metabolic Syndrome.
PubMedAnti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis.
312 Citations2006Miguel Á. González‐Gay, J M De Matias +5 more
A rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in RA patients treated periodically with this drug is confirmed and may support the longterm use of drugs that act blocking TNF-α function to reduce the mechanisms implicated in the development of atherosclerosis in patients with RA.
Current BiologyAkt and foxo Dysregulation Contribute to Infection-Induced Wasting in Drosophila
308 Citations2006Marc Dionne, Linh N Pham +2 more
This study gives insight into the metabolic consequences of infection in a genetically tractable invertebrate and implicating impaired insulin signaling as a key mediator of these events.
ScienceRequirement of JNK2 for Scavenger Receptor A-Mediated Foam Cell Formation in Atherogenesis
285 Citations2004Roméo Ricci, Grzegorz Sumara +16 more
JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis, and Macrophage-restricted deletion of JNK2 was sufficient to decrease Atherogenesis.
Proceedings of the National Academy of SciencesA genetic variant at the fatty acid-binding protein <i>aP2</i> locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease
277 Citations2006Gürol Tuncman, Ebru Erbay +5 more
Reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP1 deficiency in experimental models, and this data indicates that individuals that carry this T-87C polymorphism are partially resistant to obesity-induced insulin resistance and type 2 diabetes.
DiabetesTargeted Disruption of the Tumor Necrosis Factor-α Gene: Metabolic Consequences in Obese and Nonobese Mice
277 Citations1997John Ventre, Thomas W. Doebber +6 more
It is concluded that T NF-α functions to regulate plasma triglycerides and body adiposity and that although TNF-α contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF -α is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
Cell MetabolismMacrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions
267 Citations2006Seongah Han, Chien-Ping Liang +7 more
It is suggested that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques.
Journal of Biological ChemistryAspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases
255 Citations2003Zhan‐Guo Gao, Aamir Zuberi +3 more
Aspirin may enhance insulin sensitivity by protecting IRS proteins from serine phosphorylation catalyzed by multiple kinases, as assessed by phospho-specific antibodies.
New England Journal of MedicineChildhood Obesity and a Diabetes Epidemic
253 Citations2002Albert P. Rocchini
Data from the National Longitudinal Survey of Youth indicate that the prevalence of overweight has increased by 21.5 percent among non-Hispanic black children, 21.8 percent among Hispanic children, and 10.0 percent among preschool children in the United States since 2000.
Annals of the Rheumatic DiseasesEffects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis
252 Citations2004Dimitrios N. Kiortsis, A K Mavridis +3 more
The results suggest that infliximab treatment may have beneficial effects on insulin sensitivity in the most insulin resistant patients with RA and AS.
EndocrinologyWestern Diet Modulates Insulin Signaling, c-Jun N-Terminal Kinase Activity, and Insulin Receptor Substrate-1ser307 Phosphorylation in a Tissue-Specific Fashion
241 Citations2005Patrícia O. Prada, Henrique Gottardello Zecchin +8 more
The insulin resistance induced by WD is tissue specific and installs first in hypothalamus and muscle and later in liver, accompanied by activation of JNK and IRS-1(ser307) phosphorylation.
SciencePopulation Biology, Evolution, and Infectious Disease: Convergence and Synthesis
237 Citations1999Bruce R. Levin, Marc Lipsitch +1 more
Recent work in the genetic structure and evolution of microparasite populations, the mechanisms of pathogenesis and the immune response, and the population biology, ecology, and evolutionary consequences of medical and public health interventions are described.
Immunological ReviewsThe immune response of <i>Drosophila melanogaster</i>
220 Citations2004Vincent Leclerc, Jean‐Marc Reichhart
The cellular arm of the Drosophila innate immune system, which was somehow neglected, now constitutes the new frontier in defending against microorganism infections.
DiabetesThe Endoplasmic Reticulum Chaperone Improves Insulin Resistance in Type 2 Diabetes
210 Citations2005Kentaro Ozawa, Mayuki Miyazaki +11 more
It is suggested that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes.
Journal of Biological ChemistryTransforming Growth Factor-α Prevents Detachment-induced Inhibition of c-Src Kinase Activity, Bcl-XLDown-regulation, and Apoptosis of Intestinal Epithelial Cells
203 Citations2001Kirill V. Rosen, Mariano Loza‐Coll +2 more
It is concluded that TGF-α has the ability to suppress anoikis of intestinal epithelial cells, at least in part, by reverting the loss of c-Src activity and Bcl-XL expression induced by detachment from the ECM.
Nature GeneticsThe gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes
178 Citations2000Gérard Waeber, Jérôme Delplanque +14 more
Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of β-cell function and establishes MAPK8IP1 as a candidate gene for human diabetes.
American Journal of Physiology-Endocrinology and MetabolismInfluence of TNF-α and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans
176 Citations2006Rikke Krogh‐Madsen, Peter Plomgaard +3 more
Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-α and interleukin (IL-6) may affect glucose uptake.
Journal of Clinical InvestigationThe adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation
153 Citations2006Bennett O. V. Shum
Analysis of bone marrow chimeras implicated non-hematopoietic cells, most likely bronchial epithelial cells, as the site of action of aP2 in allergic airway inflammation and may provide a link between fatty acid metabolism and asthma.
HepatologyImpact of obesity on treatment of chronic hepatitis C†
137 Citations2006Michael Charlton, Paul J. Pockros +1 more
The mechanisms by which obesity may be associated with decreased efficacy of interferon‐based therapies in individuals with chronic hepatitis C are reviewed and the therapeutic strategies that may increase the effectiveness of these therapies in obese individuals are reviewed.
Cell MetabolismMyeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis
126 Citations2006Julia Baumgartl, Stephanie Baudler +11 more
Significant differences in the effects of systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis are provided, providing direct evidence that myeloids lineage autonomous insulin signaling provides proinflammatory signals predisposing to the Development of Atherosclerosis.
Molecular CellNF-κB Is Required for UV-Induced JNK Activation via Induction of PKCδ
100 Citations2006Jing Liu, Dan Yang +4 more
The results demonstrate that RelA/NF-kappaB via PKCdelta positively regulates UV-induced JNK activation and provide a mechanism by which NF- kappaB promotes UV- induced apoptosis.
ScienceFunctional Delivery of a Cytosolic tRNA into Mutant Mitochondria of Human Cells
99 Citations2006Bidesh Mahata, Saikat Mukherjee +3 more
It is found that the Leishmania RNA import complex (RIC) could enter human cells by a caveolin-1–dependent pathway, where it induced import of endogenous cytosolic tRNAs, including tRNALys, and restored mitochondrial function in a cybrid harboring a mutant mt tRNalys (MT-TK) gene.
…