1927-P: Protective Role of DNAJB3 Cochaperone against Obesity-Induced Insulin Resistance and Diabetes

The last decade has witnessed a dramatic increase in the prevalence of obesity and type 2 diabetes (T2D) in some Middle Eastern countries. In the GCC countries, over 35% and 20% develop obesity and T2D, respectively. Of extreme concern, the disease starts affecting the population at a relatively younger age (∼40 years), and vulnerable individuals manifest severe insulin resistance (IR). We previously showed that subjects with obesity and T2D among the Kuwaiti population have reduced expression of DNAJB3 that was associated with increased metabolic stress and poor clinical outcomes. Furthermore, physical exercise was effective in restoring the normal expression of DNAJB3 with the concomitant metabolic improvements. These observations suggest a therapeutic value of DNAJB3 against obesity-associated metabolic diseases. To gain further insights into this protective role, we generated mice lacking DNAJB3 using CRISPR/Cas9 approach, and challenged them with high fat diet (HFD). We also determined the in vitro effects of DNAJB3 overexpression/knockdown in modulating metabolic stress, mitochondrial and glucose homeostasis in C2C12 cells. Accordingly, DNAJB3 KO mice showed increased body weight and fat mass in response to HFD, compared to wild type. In addition, DNAJB3 KO mice on HFD exhibited increased glucose intolerance. Moreover, overexpression of DNAJB3 prevented the activation of both JNK and IKK in response to palmitate and inflammatory cytokines, respectively; while it promoted the PI3K/AKT pathway and both basal and insulin-stimulated glucose uptake. These observations were consistent with DNAJB3 knockdown experiments. Mechanistically, we showed a significant effect of DNAJB3 on enhancing Glut4 translocation and stimulating expression of key mitochondrial markers including PPARγ, PGC1α and OXPHOS. Together, these data indicate an important physiological role of DNAJB3 in obesity-induced IR and T2D and warrant further in vivo animal and clinical investigations. Disclosure M. Dehbi: None. A. Diane: None. S. Scoggin: None. I. Bensmail: None. N. Khattab: None. L. Ramalingam: None. A. Efotte: None. N. Moustaid-Moussa: None. Funding Qatar Biomedical Research Institute (IGP 2014-001)