DNAJB3 Deficiency in Mice, Sex-Dependently, Exacerbates High-Fat Diet-Induced Metabolic Dysfunctions

Objective: DNAJB3, a heat shock protein, plays a critical role in metabolic aberrations associated with obesity and type 2 diabetes (T2D). This study investigated how DNAJB3 deficiency exacerbates inflammation and glucose intolerance in diet-induced obese mice. Methods: Male and female DNAJB3 knockout (KO) and wild-type (WT) mice were fed high-sucrose (17 kcal%) and high-fat (HF: 45 kcal%) or low-fat (LF: 10 kcal%) diets for 12 weeks. Body weight, food intake, glucose tolerance, and energy expenditure were assessed; blood, adipose, and liver tissues were collected for histological and gene expression analyses. Results: HF-fed KO females exhibited higher body and fat mass and lower glucose clearance and energy expenditure, compared to other groups. Males showed a clear HF diet effect across both genotypes. Increased serum leptin, interleukin 6, and insulin levels were observed in HF-KO females, while HF-KO males showed higher leptin and resistin levels compared to other groups. Additionally, inflammatory and glucose transporter gene expression was altered by DNAJB3 deficiency in adipose tissues and the pancreas, highlighting the impaired glucose metabolism. Conclusions: These findings suggest the importance of DNAJB3 in glucose and metabolic regulation, especially in females, and its potential use as a therapeutic target for obesity and T2D.