Skeletal Muscle Tissue Trib3 Links Obesity with Insulin Resistance by Autophagic Degradation of AKT2

Cell Physiol Biochem. 2018;48(4):1543-1555. doi: 10.1159/000492264. Epub 2018 Aug 2.


Background/aims: Obesity is a serious health risk factor strongly associated with insulin resistance and type 2 diabetes; however, the underlying mechanisms associating obesity with insulin resistance remain unknown. In this study, we explored the physiological role of Trib3 in regulating glucose metabolism in skeletal muscle tissues in a Trib3 transgenic mice model.

Methods: Glucose metabolism in transgenic mice overexpressing Trib3 specifically in the skeletal muscle was examined by glucose/insulin tolerance test, metabolic cage studies, and glucose uptake assay. The effect of Trib3 overexpression on AKT phosphorylation and AKT protein turnover were assessed by RT-PCR and immunoblot analysis. Subcellular distribution of Trib3 and AKT1/2 was determined by microscopic analysis, co-immunoprecipitation experiments, and limited-detergent extraction of subcellular organelles. Ubiquitin assay was performed and ATG7 deficient cell line was employed to address the mechanisms of Trib3-dependent AKT protein homeostasis.

Results: We found that Trib3 expression in skeletal muscle is elevated in obese conditions, and transgenic mice that overexpressed Trib3, specifically in skeletal muscle tissues, displayed impaired glucose homeostasis by suppressing insulin-stimulated glucose uptake. Disruption of insulin signaling in skeletal muscle Trib3 transgenic mice may occur due to the specific downregulation of AKT2 but not AKT1. Autophagy regulated AKT2 protein turnover, and Trib3 overexpression stimulated autophagic degradation of AKT2 by promoting AKT2 ubiquitination.

Conclusion: Because diet-induced obesity upregulates Trib3 and downregulates AKT2 in skeletal muscle tissues, Trib3 may play a key role in establishing an association between obesity and insulin resistance by regulating AKT2 protein homeostasis.

Keywords: AKT2; Autophagy; Insulin resistance; Obesity; Tribbles.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / pathology
  • Diet, High-Fat
  • Glucose / metabolism
  • Glucose Tolerance Test
  • HeLa Cells
  • Humans
  • Insulin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism
  • Obesity / pathology*
  • Obesity / veterinary
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction


  • Cell Cycle Proteins
  • Insulin
  • TRB3 protein, mouse
  • Akt1 protein, mouse
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glucose