ABSTRACT
Pancreatic ß cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.
Subject(s)
Brain , Drosophila Proteins , Drosophila melanogaster , Insulin Secretion , Insulin , Animals , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Brain/metabolism , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Brain-Gut Axis/physiology , Lipase/metabolism , Lipase/genetics , Dietary Fats/metabolism , Glucose/metabolism , Fat Body/metabolism , Lipoprotein Lipase/metabolism , Lipoprotein Lipase/genetics , MaleABSTRACT
T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.
Subject(s)
Cell Differentiation , Encephalomyelitis, Autoimmune, Experimental , Serine C-Palmitoyltransferase , Sphingolipids , Th17 Cells , Animals , Sphingolipids/metabolism , Sphingolipids/biosynthesis , Th17 Cells/immunology , Th17 Cells/metabolism , Th17 Cells/cytology , Mice , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/immunology , Serine C-Palmitoyltransferase/metabolism , Serine C-Palmitoyltransferase/genetics , Reactive Oxygen Species/metabolism , Glycolysis , Mice, Knockout , Colitis/metabolism , Colitis/pathology , Mice, Inbred C57BLABSTRACT
As entomopathogenic viruses, mosquito densoviruses (MDVs) are widely studied for their potential as biocontrol agents and molecular laboratory tools for mosquito manipulation. The nucleus of the mosquito cell is the site for MDV genome replication and capsid assembly, however the nuclear localization signals (NLSs) and nuclear export signals (NES) for MDV proteins have not yet been identified. We carried out an in silico analysis to identify putative NLSs and NESs in the viral proteins of densoviruses that infect diverse mosquito genera (Aedes, Anopheles, and Culex) and identified putative phosphorylation and glycosylation sites on these proteins. These analyses lead to a more comprehensive understanding of how MDVs are transported into and out of the nucleus and lay the foundation for the potential use of densoviruses in mosquito control and basic research.