A central role for JNK in obesity and insulin resistance

  title={A central role for JNK in obesity and insulin resistance},
  author={Jiro Hirosumi and Gurol Tuncman and Lufen Chang and Cem Z. G{\"o}rg{\"u}n and K. Teoman Uysal and Kazuhisa Maeda and Michael Karin and G{\^o}khan S. Hotamisligil},
Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity… 
Inflammation and endoplasmic reticulum stress in obesity and diabetes
ER stress and the related signaling networks present a critical mechanism underlying obesity-induced JNK activity, inflammatory response and insulin resistance.
Macrophages, inflammation, and insulin resistance.
Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.
The JNK pathway as a therapeutic target for diabetes
  • H. Kaneto
  • Biology, Medicine
    Expert opinion on therapeutic targets
  • 2005
Taking together, the JNK pathway is likely to play a central role in the progression of insulin resistance and β-cell dysfunc-tion and, thus, could be a potential therapeutic target for diabe-tes.
Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D.
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
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).
Novel roles for JNK1 in metabolism
Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other
Insulin sensitivity: modulation by nutrients and inflammation.
The hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity is focused on, which provides the integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.
The current biology of resistin
This review will summarize the current understanding of resistin and will attempt to provide a framework for future study of its role in rodent and human physiology.
The role of TNF-α in insulin resistance
This review will discuss the regulation of insulin responses by TNF-α and evidence supporting the hypothesis that over expression of T NF-α plays a role in the pathophysiology of insulin resistance, and discuss the role of fat, especially visceral fat, as an endocrine organ.
The Role of JNk Signaling Pathway in Obesity-Driven Insulin Resistance
  • Jia FengShiyin Lu Yi Ma
  • Biology
    Diabetes, metabolic syndrome and obesity : targets and therapy
  • 2020
An overview of the composition of the JNK signaling pathways, its regulation of insulin signaling pathway, and the relationship between the J NK signaling pathway and other pathways in insulin resistance is provided.


Protection from obesity-induced insulin resistance in mice lacking TNF-α function
Results indicate that TNF-α is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
The hormone resistin links obesity to diabetes
It is shown that adipocytes secrete a unique signalling molecule, which is named resistin (for resistance to insulin), which circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity.
Insulin signalling and the regulation of glucose and lipid metabolism
The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less
Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM
Continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.
The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity
It is concluded that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy and that the replenishment of adiponECTin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance
Results indicate that TNF-α induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
The role of TNF alpha in adipocyte metabolism.
In adipose tissue, in particular, TNF alpha has been demonstrated to regulate or interfere with adipocyte metabolism at numerous sites including transcriptional regulation, glucose and fatty acid metabolism and hormone receptor signaling.
Improved Glucose and Lipid Metabolism in Genetically Obese Mice Lacking aP2.
The data indicate that in obesity, aP2-deficiency not only improves peripheral insulin resistance but also preserves pancreatic b cell function and has beneficial effects on lipid metabolism.
Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
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.
Cellular mechanisms of insulin resistance.
  • G. Shulman
  • Biology
    The Journal of clinical investigation
  • 2000
It is shown that commonly accepted models that attempt to explain the association of insulin resistance and obesity are incompatible with recent findings and an alternative model is proposed that appears to fit these and other available data.