Overexpression of the short isoform of the dopamine <scp>D2</scp> receptor causes diet‐induced obesity and hyperglycemia in mice

Dopamine and dopamine D2R receptors (D2R) are involved in regulating eating behavior and endocrine and metabolic functions. D2R exists in two D2R isoforms: D2L (long form) and D2S (short form). Little is known if the changes in the expression levels of D2S and D2L would cause metabolic alterations. Here, we examined the role of these two D2R isoforms in obesity and glucose homeostasis. Mice of two genotypes were fed a higher fat diet (HFD). Body weight and food intake were monitored chronically, and various fat pads were dissected. Glucose tolerance and insulin tolerance tests were conducted. Energy expenditure and respiratory exchange ratio were measured via indirect calorimetry. We found when feeding with HFD, dopamine D2L knockout (D2L KO) mice (expressing purely D2S) of both female and male gained significantly more body weight than wild-type (WT) mice (expressing predominantly D2L) of both sexes. In addition, when feeding HFD, D2L KO mice showed an increased food intake compared to WT mice. Furthermore, when feeding HFD, both female and male D2L KO mice displayed impaired glucose tolerance. There were no significant differences in energy expenditure, respiratory quotient, and insulin sensitivity between D2L KO and WT mice. These results suggest that an increased expression level of D2S to D2L makes mice prone to obesity and hyperglycemia. Our findings identify a new risk factor contributing to the development of metabolic syndrome and increase our understanding of pathophysiological mechanisms leading to weight gain and diabetes.