The role of Arginyltransferase 1 in body weight homeostasis

August 2023
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Previous studies reported that systemic deletion of Arginyltransferase 1 (ATE1) in mice results in dramatic fat loss and resistance to diet-induced obesity. However, the mechanisms through which ATE1 influence energy metabolism remain unclear. Here, we investigated the hypothalamic role of ATE1 by examining the effects of the anorectic hormone leptin in wild type (WT) and ATE1-knockout (ATE1-KO) mice maintained on a normal chow diet, or a high fat diet. We found that on both diets, ATE1-KO mice weighed significantly less than WT mice despite consuming more food (hyperphagia). We also found that, similar to WT mice on normal chow, ATE1-KO mice remain responsive to leptin on NC. However, ATE1-KO mice had significantly lower circulating plasma leptin than wild type mice on both diets. This explains (at least in part) their hyperphagia. Interestingly, we also found that leptin reduces the expression of ATE1 in the hypothalamus, indicating that decreased ATE1 activity may be a component of the Leptin regulatory network driving a lean phenotype. In contrast to normal chow, we found that ATE1-KO mice became leptin resistant on high fat diet. Remarkably, we found that the loss of Ate1 gene function reverses high fat diet-induced obesity. Collectively, these results strongly suggest that the inhibition of ATE1 may offer an effective therapeutic strategy to combat obesity.

Arginyltransferase 1; ATE1; obesity; fat loss