The Effect of DNAJB3 Deficiency on Metabolic Dysfunctions in Diet-induced Obese Mice

Abstract

Abstract Objectives Obesity and related metabolic dysfunctions are partly mediated by chronic low-grade inflammation and altered expression of numerous proteins including stress responsive heat shock proteins (HSPs). We are specifically interested in HSP40 (Heat Shock Protein-40), subfamily B, member 3 (DNAJB3), a chaperone protein that aids in restoring protein homeostasis. Patients with obesity and type 2 diabetes (T2D) expressed low levels of DNAJB3, which was partly restored by physical activity. Accordingly, we hypothesized that lack of DNAJB3 will increase body weight, inflammation, glucose intolerance and insulin resistance in diet-induced obese mice, compared to B6 wild type (WT) littermates fed the same diets. Methods DNAJB3 knockout (KO) mice were generated using the CRISPR/Cas 9 approach. Male and female KO and wild type (WT) mice were fed high fat (HF: 45 kcal% fat) or low fat (LF: 10 kcal% fat) diets for 12 weeks. Body weight and food intake were measured weekly; body composition measurements and glucose tolerance tests were also conducted during the intervention. Following euthanasia, blood, and tissues were harvested for further analyses. Serum adipokines and hormones were measured using a multiplex immunoassay. Results Compared to WT male and female, KO mice fed HF diets demonstrated higher body weight and fat mass. Similarly, both male and female KO HF groups demonstrated a slower glucose clearance rate as measured by GTT compared to the LF KO and WT groups as well as HF WT groups. Interestingly, these findings were more significant across the board in the female HF-KO group. Female HF group demonstrated a higher leptin, IL-6 and Insulin levels compared to the other groups (p < 0.0001). Additionally, Male Leptin and Resistin levels were higher in the HF-KO group compared to the other groups (p = 0.0001, p = 0.0253). Conclusions Lack of DNAJB3, increases adiposity and glucose intolerance in diet-induced obese male and female mice. Thus, DNAJB3 potentially plays an important role in metabolic functions and glucose homeostasis, warranting further research on DNAJB3 as a potential therapeutic target for obesity and T2D. Funding Sources Funded by Qatar National Research Funds, Hamad Bin Khalifa University & Qatar Biomedical Research Institute, Qatar.