Contributing to the obesity epidemic, there is increasing evidence that overconsumption of high-fat foods may be analogous to drug addiction in that the palatability of these foods is associated with activation of specific reward pathways in the brain. With this perspective, we report that mice lacking the G protein gamma(3)-subunit (Gng3(-/-) mice) show resistance to high-fat diet-induced weight gain over the course of a 12-wk study. Compared with Gng3(+/+) controls, female Gng3(-/-) mice exhibit a 40% reduction in weight gain and a 53% decrease in fat pad mass, whereas male Gng3(-/-) mice display an 18% reduction in weight gain and no significant decrease in fat pad mass. The basis for the lowered weight gain is related to reduced food consumption for female and male Gng3(-/-) mice of 13% and 14%, respectively. Female Gng3(-/-) mice also show a lesser preference for high-fat chow than their female Gng3(+/+) littermates, suggesting an attenuated effect on a reward pathway associated with overconsumption of fat. One possible candidate is the micro-opioid receptor (Oprm1) signaling cascade. Supporting a defect in this signaling pathway, Gng3(-/-) mice show marked reductions in both acute and chronic morphine responsiveness, as well as increases in endogenous opioid mRNA levels in reward-related regions of the brain. Taken together, these data suggest that the decreased weight gain of Gng3(-/-) mice may be related to a reduced rewarding effect of the high-fat diet resulting from a defect in Oprm1 signaling and loss of the G protein gamma(3)-subunit.