dakh-peptide and Starvation

The role of adipokinetic hormone (Drome-AKH) in maintaining the levels of basic nutrients, under starvation conditions, was studied using Drosophila melanogaster mutants with AKH deficiency (Akh

Topics: Animals; Animals, Genetically Modified; Carbohydrate Metabolism; Crosses, Genetic; Diglycerides; Drosophila melanogaster; Drosophila Proteins; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Female; Gene Deletion; Glycogen; Insect Hormones; Lipid Metabolism; Male; Oligopeptides; Pyrrolidonecarboxylic Acid; Random Allocation; Reproducibility of Results; Sex Characteristics; Starvation; Survival Analysis; Triglycerides

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.

Topics: Acid Anhydride Hydrolases; Amygdala; Animals; Cell Line, Tumor; Drosophila; Drosophila Proteins; Gene Knockdown Techniques; HCT116 Cells; HeLa Cells; Humans; Hyperinsulinism; Hyperphagia; Hypothalamus; Insect Hormones; Insulin; Insulin-Secreting Cells; Intercellular Signaling Peptides and Proteins; Male; MCF-7 Cells; Mice; Mice, Inbred C57BL; Obesity; Oligopeptides; Pyrophosphatases; Pyrrolidonecarboxylic Acid; RNA, Messenger; Signal Transduction; Somatomedins; Starvation; Trehalose