dakh-peptide and Disease-Models--Animal

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

While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-β (Actβ), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is upregulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control.

Topics: Activin Receptors; Activins; Animals; Carbohydrate Metabolism; Carrier Proteins; Dietary Carbohydrates; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Enteroendocrine Cells; Fat Body; Gastrointestinal Tract; Glucagon; Hepatocytes; Hyperglycemia; Insect Hormones; Larva; Mice; Oligopeptides; Pyrrolidonecarboxylic Acid; Receptors, Glucagon; RNA Interference; RNA, Messenger; Signal Transduction