ArticleMolecular metabolism2015
Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity.
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Pooled it
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- The role of ubiquitination and deubiquitination in the pathogenesis of non-alcoholic fatty liver disease.Frontiers in immunology · 2025Review
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- Progress and Prospects of Non-Canonical NF-κB Signaling Pathway in the Regulation of Liver Diseases.Molecules (Basel, Switzerland) · 2022Review
- The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis.Frontiers in cardiovascular medicine · 2022Review
- Evaluation of the Mechanism of Modified Lingguizhugan Decoction in the Treatment of Nonalcoholic Fatty Liver Disease.Evidence-based complementary and alternative medicine : eCAM · 2022Article
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- Caveolin-1 Is Essential for the Improvement of Insulin Sensitivity through AKT Activation during Glargine Treatment on Diabetic Mice.Journal of diabetes research · 2021Article
- Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality.Nature metabolism · 2020Article
- Purβ promotes hepatic glucose production by increasing Adcy6 transcription.Molecular metabolism · 2020Article
- Innate immune regulatory networks in hepatic lipid metabolism.Journal of molecular medicine (Berlin, Germany) · 2019Review
- Preconditioning lessens high fat induced metabolic syndrome along with markers of increased metabolic capacity in muscle and adipose tissue.Bioscience reports · 2018Article
- TRAF molecules in inflammation and inflammatory diseases.Current pharmacology reports · 2018Article
- TRAF3 as a Multifaceted Regulator of B Lymphocyte Survival and Activation.Frontiers in immunology · 2018Review
- Recent advances of adapter proteins in the regulation of heart diseases.Heart failure reviews · 2017Review
- TRAF3 deficiency promotes metabolic reprogramming in B cells.Scientific reports · 2016Article
- A long non-coding RNA, APOA4-AS, regulates APOA4 expression depending on HuR in mice.Nucleic acids research · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
objectiveMetabolic inflammation is believed to promote insulin resistance and type 2 diabetes progression in obesity. TRAF3, a cytoplasmic signaling protein, has been known to mediate/modulate cytokine signaling in immune cells. The goal is to define the metabolic function of hepatic TRAF3 in the setting of obesity.
methodsHepatocyte-specific TRAF3 knockout mice were generated using the loxp/albumin-cre system. Liver TRAF3 was deleted in adult obese mice via Cre adenoviral infection. Both high fat diet-induced and genetic obesity were examined. TRAF3 levels and insulin signaling were measured by immunoblotting. Insulin sensitivity, hepatic glucose production, and glucose metabolism were examined by glucose, insulin, and pyruvate tolerance tests. Hepatic steatosis was examined by Oil red O staining of liver sections and measuring liver triacylglycerol levels.
resultsLiver TRAF3 levels were lower in the fasted states in normal mice, and were aberrantly higher in obese mice and in mice with streptozotocin-induced hyperglycemia. Glucose directly increased TRAF3 levels in primary hepatocytes. Hepatocyte-specific deletion of TRAF3 decreased hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis in mice with either high fat diet-induced obesity or genetic obesity (ob/ob); conversely, in lean mice, adenovirus-mediated overexpression of TRAF3 in the liver induced hyperinsulinemia, insulin resistance, and glucose intolerance. Deletion of TRAF3 enhanced the ability of insulin to stimulate phosphorylation of Akt in hepatocytes, whereas overexpression of TRAF3 suppressed insulin signaling.
conclusionsGlucose increases the levels of hepatic TRAF3. TRAF3 in turn promotes hyperglycemia through increasing hepatic glucose production, thus forming a glucose-TRAF3 reinforcement loop in the liver. This positive feedback loop may drive the progression of type 2 diabetes and nonalcoholic fatty liver disease in obesity.
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