From Selection Signatures in Cattle to Functional Validation in Mice: HSPA12B Negatively Regulates Adipose Browning and Thermogenesis

Lay Summary How do animals adapt to cold? This study identifies HSPA12B as a key “brake gene” regulating cold resistance. Evolutionary analysis revealed strong natural selection for HSPA12B in cold-tolerant cattle breeds from northern China and the Tibetan Plateau, linking it to cold adaptation. The gene is highly active in heat-producing brown adipose tissue. To test its function, researchers created mice lacking Hspa12b gene. These mice exhibited enhanced conversion of white fat into energy-burning beige fat (browning), resulting in higher body temperatures, improved cold tolerance, better blood sugar control, and increased insulin sensitivity—indicating healthier metabolism and reduced obesity/diabetes susceptibility. Mechanistically, HSPA12B acts as a “negative regulatory switch” suppressing fat browning and thermogenesis; its deletion removes this brake, allowing adipose tissue to actively burn energy for warmth. This process involves regulation of the thermogenic gene Elovl3. The findings uncover a molecular mechanism for mammalian cold adaptation and position HSPA12B inhibition as a novel therapeutic strategy against human metabolic disorders like obesity and diabetes by promoting efficient fat burning.