dakh-peptide and Hyperphagia

Obesity is a progressive, chronic disease, which can be caused by long-term miscommunication between organs. It remains challenging to understand how chronic dysfunction in a particular tissue remotely impairs other organs to eventually imbalance organismal energy homeostasis. Here we introduce RNAi Pulse Induction (RiPI) mediated by short hairpin RNA (shRiPI) or double-stranded RNA (dsRiPI) to generate chronic, organ-specific gene knockdown in the adult Drosophila fat tissue. We show that organ-restricted RiPI targeting Stromal interaction molecule (Stim), an essential factor of store-operated calcium entry (SOCE), results in progressive fat accumulation in fly adipose tissue. Chronic SOCE-dependent adipose tissue dysfunction manifests in considerable changes of the fat cell transcriptome profile, and in resistance to the glucagon-like Adipokinetic hormone (Akh) signaling. Remotely, the adipose tissue dysfunction promotes hyperphagia likely via increased secretion of Akh from the neuroendocrine system. Collectively, our study presents a novel in vivo paradigm in the fly, which is widely applicable to model and functionally analyze inter-organ communication processes in chronic diseases.

Topics: Adipose Tissue; Animals; Aspartate Aminotransferase, Cytoplasmic; Calcium; Calcium Signaling; Calcium-Binding Proteins; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Energy Metabolism; Female; Gene Expression Regulation; Homeostasis; Humans; Hyperphagia; Insect Hormones; Ion Transport; Isoenzymes; Lipid Metabolism; Malate Dehydrogenase; Male; Obesity; Oligopeptides; Pyrrolidonecarboxylic Acid; RNA, Small Interfering; Stromal Interaction Molecule 1

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