Constitutively active glucagon receptor (GCGR) physiologically regulates body temperature in lizards

Endotherms use complex internal mechanisms to maintain a steady body temperature, whereas ectotherms rely on environmental factors and behaviors for thermoregulation. Certain ectothermic animals, like some lizards, can also physiologically regulate their body temperature to some extent, with interspecies variations in thermoregulatory capacity under low-temperature conditions. However, the molecular mechanisms underlying this physiological regulation have remained unclear since its discovery about 80 years ago. Here, we reveal that the hepatic expression of constitutively active glucagon receptor (GCGR) in lizards, particularly in iguana, correlated with their thermoregulatory capacity when kept at low temperatures. When Pogona vitticeps and Phrynocephalus vlangalii with thermoregulatory capacity were treated with short hairpin RNA-GCGR or GCGR antagonist, their body temperatures dropped, and the expression of genes related to energy metabolism and respiratory metabolic rate was down-regulated. In contrast, Eremias argus, lacking thermoregulatory ability, revealed low hepatic GCGR expression. Overexpression of P. vitticeps GCGR (pvGCGR) in the liver of E. argus increased body temperature and enhanced energy metabolism. Furthermore, in mice with reduced thermoregulatory ability by chlorpromazine administration, overexpression of constitutively active GCGR ligand-independently increased body temperature under cold conditions. In conclusion, constitutively active GCGR drives the physiological thermoregulation in lizards, and our study offered previously unidentified insights into expression regulation of constitutively active GPCR into physiological adaptations responding to environmental changes.