Figure 9. Schematic representation of the effect of Gja1 ablation on the metabolic response to an HFD.

Left column: In normal mice, high dietary calorie intake changes energy metabolism, resulting in excess energy storage in fat depots and other organs, leading to obesity, hyperinsulinemia, high serum lipids, and glucose intolerance. In WAT depots (bottom row), fat accumulation occurs primarily by adipocyte hypertrophy; in BAT (top row), it leads to whitening as cells become engulfed by lipid droplets. Right column: Genetic ablation of Gja1 in the mesenchymal lineage (cKO^Tw2) mitigates these effects of high calorie intake, resulting in reduced BAT whitening and higher BAT activity (increased lipolysis, fatty acid oxidation, and oxidative phosphorylation), smaller WAT depots, and increased glucose uptake and utilization. At the organism level (middle row), Cx43-deficient mice are more active and more cold tolerant, burn more energy, and utilize more glucose than control littermates under high calorie intake. We propose that the increased energy consumption for physical activity and thermogenesis reduces fat accumulation, WAT hypertrophy, and BAT whitening, resulting in less severe obesity, partially preserved glucose tolerance, and better circulating lipid profile than in normal mice.