Previous studies have shown that deletion or downregulation of ATE1 can lead to neurodegeneration, behavioral abnormalities, hyperphagia and lower body weight. To determine how loss of ATE1 affects energy metabolism and food intake, ATE1-deficient and ATE1-containing mice were given high fat diet for 12 weeks. Based on our current data, we found significant sex differences in body weight and food intakes, with ATE1-deficient mice less sensitive to the obesogenic effects of high fat diet even while consuming the same amount of high fat diet as controls. Interestingly, ATE1-deficient mice exposed to high fat diet displayed lower plasma leptin levels. Leptin-treated ATE1-deficient mice show changes in pSTAT3 expression in the arcuate nucleus of the hypothalamus relative to leptin-treated ATE1-containing mice. Lastly, diet-induced obesity can be ameliorated by tamoxifen-induced knockout of ATE1 in adult male mice relative to vehicle-treated WT mice. Taken together, these data indicate that loss of ATE1 produces attenuated leptin levels in mouse models of diet-induced obesity and can mitigate the effects of high fat diet. NIGMS, 1SC1GM144190-01 (ESN), NINDS R15NS095317 (CSB), Texas Woman's University internal funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.