Abstract
Failure of the heat shock response is a key event that leads to insulin resistance and type 2 diabetes. We recently showed that DNAJB3 co-chaperone is downregulated in obese and diabetic patients and that physical exercise restores its normal expression with a significant improvement of the clinical outcomes. In 3T3-L1 adipocytes, DNAJB3 has a role in improving the sensitivity to insulin and glucose uptake. In co-immunoprecipitation assays, DNAJB3 interacts with both JNK1 and IKKβ kinases. However, the functional impact of such interaction on their activities has not been investigated. Here, we assessed the effect of DNAJB3 on the respective activity of JNK1 and IKKβ in cell-based assays. Using JNK1- and IKKβ-dependent luciferase reporters, we show a marked decrease in luciferase activity by DNAJB3 in response to PMA and TNF-α that was consistent with a decrease in the translocation of p65/NF-κB to the nucleus in response to LPS. Furthermore, TNF-α-mediated IL-6 promoter activation and endogenous mRNA expression are significantly abrogated by DNAJB3 both in 3T3-L1 and C2C12 cells. The ability of DNAJB3 to mitigate ER stress and oxidative stress was also investigated and our data show a significant improvement of both forms of stress. Finally, we examined the effect of overexpressing and knocking down the expression of DNAJB3 on glucose uptake in C2C12 as well as the molecular determinants. Accordingly, we provide evidence for a role of DNAJB3 in promoting both basal and insulin-stimulated glucose uptake. Our finding reveals also a novel role of DNAJB3 in eliciting Glut4 translocation to the plasma membrane. These results suggest a physiological role of DNAJB3 in mitigating metabolic stress and improving glucose homeostasis and could therefore represent a novel therapeutic target for type 2 diabetes.
Highlights
Type 2 diabetes is a multifactorial metabolic disorder characterized by chronic hyperglycemia secondary to either increased insulin resistance (IR) in peripheral organs, progressive failure of the pancreatic islet β-cells or both[1]
We recently reported the impaired expression of DNAJB3 cochaperone in adipose tissue biopsies isolated from obese non-diabetic[11] and diabetic[23] subjects, and that low levels of DNAJB3 were associated with enhanced metabolic stress[23]
Using JNK1- and IKKβ-dependent luciferase reporters, we show a significant decrease in luciferase activity by DNAJB3 in response to phorbol myristate acetate (PMA) and tumor necrosis factor-α (TNF-α)
Summary
Type 2 diabetes is a multifactorial metabolic disorder characterized by chronic hyperglycemia secondary to either increased insulin resistance (IR) in peripheral organs, progressive failure of the pancreatic islet β-cells or both[1]. Metabolic stress is a prominent hallmark underlying both obesity and type 2 diabetes and it consists of a constellation of stress responses that are dysregulated in metabolically relevant sites This include chronic metaflammation[4], glucolipotoxicity[5], increased oxidative stress[6], mitochondrial dysfunction or biogenesis[7], and persistent ER stress[8] with the concomitant impairment of the anti-inflammatory response[9], anti-oxidant defense system[10] and the heat shock response (HSR)[11,12]. Subsequent studies demonstrated that some of the HSPs (i.e. HSP-25 and HSP-72) act as natural inhibitors of JNK and IKKβ kinases and they exhibit anti-apoptotic, anti-inflammatory and anti-oxidative stress properties[17,18,19] In this regards, interventions that activate the HSR system are being intensively explored as alternative strategies to mitigate damages resulting from various stressful conditions including metabolic diseases[20,21,22].
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