GJB2 encodes connexin 26 (Cx26), and pathogenic GJB2 variants are among the most common genetic causes of hereditary hearing loss; because Cx26 is expressed in metabolically relevant tissues including liver, pancreas, and adipose tissue, whether the hearing-loss-associated c.109G>A (p.V37M) variant also modifies systemic metabolic responses to high-fat diet (HFD) exposure remains unclear. Three-month-old male wild-type (WT) and homozygous Gjb2 V37M mice were assigned to low-fat diet (LFD) or high-fat diet (HFD) groups, generating four study groups: WT-LFD, WT-HFD, V37M-LFD, and V37M-HFD. The mice were followed until 12 months of age, with dietary intervention continued for 9 months. Body weight, body mass index (BMI), fasting blood glucose, serum triglycerides, and HDL cholesterol were assessed at 3, 6, 9, and 12 months. An oral glucose tolerance test was performed at 9 months, and omental fat was measured at 12 months. WT-HFD mice showed marked progressive increases in body weight and BMI, whereas increases were less pronounced in V37M-HFD mice. At 12 months, body weight and BMI did not differ significantly between V37M-LFD and V37M-HFD mice. Fasting glucose, glucose tolerance, triglyceride, and HDL cholesterol profiles differed among groups. Omental fat weight also differed significantly, although the only significant post hoc comparison was between WT-HFD and V37M-LFD mice. These findings indicate that