Several genome-wide association studies have linked the
Nudix hydrolase family member
nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to
obesity. However, the manner of NUDT3 involvement in
obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3
mRNA and
protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3
mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the
insulin-producing cells (IPCs), induces
hyperinsulinemia-like phenotypes, including a decrease in circulating
trehalose levels as well as significantly decreasing all
carbohydrate levels under
starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these
lipids during
starvation. Also, loss of neuronal Aps expression caused a
starvation susceptibility phenotype while inducing
hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, Ilp6, and Ilp3, genes known to be inhibited by
insulin signaling. These results point toward a role for this gene in the regulation of
insulin signaling, which could explain the robust association with
obesity in humans.