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Principal Investigator: PETER Kent JACKSON
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $484,046
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
This project focuses on understanding how dietary fluxes from w-3 fatty acids activate the FFAR4
receptor, expressed in primary cilia, in both preadipocytes to trigger adipogenesis and in pancreatic b cells to enhance insulin secretion. The proposal extends from a recent discovery in the Jackson lab of a dramatic requirement for primary cilia in de novo adipogenesis and for the accumulation of fat mass in mice (Cell 2019). Using a knockout of TULP3, a critical regulator of ciliary GPCR trafficking, the group has established a requirement for ciliary GPCR signaling and screened 36 candidates to discover that the w-3 fatty acid (FA) receptor FFAR4/GPR120 is critical. Using FFAR4 and ciliary markers, the group finds that ciliated FFAR4+ preadipocytes comprise a perivascular stem cell population in all fat pads. Further, DHA-FFAR4 signaling synergizes with insulin signaling to direct adipogenic fate change and that FFAR4 agonists rapidly activate localized cAMP in the cilium. To better define the steps in adipogenesis downstream of FFAR4, two genome-wide CRISPR screens for genes important in adipogenesis were conducted, one using a traditional adipogenesis formulation and the other activated by FFAR4 agonists. These screens recapitulated most known requirements
for adipogenesis and provided a wealth of new genes important for the adipogenic program. Among these there is a strong requirement for new factors controlling translation initiation and cap-independent translation. Finally, looking for the importance of FFAR4 in other metabolic systems, the group discovered that all pancreatic islet cell types are ciliated, but that both b and a cells express FFAR4 in cilia. Detailed pharmacology and genetics show that FFAR4 agonists can drive glucose stimulated insulin secretion (GSIS) in isolated b cells or islets at levels comparable to known secretagogues like GLP-1. FFAR4 agonists also stimulate glucagon secretion in a cells. Both effects require ciliary trafficking. The first Aim will focus on validating and explaining new adipogenesis factors found in the screen. This will focus on identifying specific adenylate cyclases, phosphodiesterases, cAMP effectors, and translational control genes. Aim 2 will focus on FFAR4 signaling in pancreatic b cells to understand the mechanisms of how FFAR4 and cAMP drive insulin secretion and how another w-3 fatty acid receptor, FFAR1, drives calcium influx to cooperate with FFAR4. Finally, in Aim 3, the focus is to use mouse models systematically knocking out both FFAR4 and FFAR1 to examine the cooperation of these pathways in obesity, insulin secretion and diabetes. This aim will also examine human patient adipose tissue to determine if FFAR4+ ciliary in preadipocytes are lost in aging, diabetic or obese patients, also comparing sex differences. Overall, Aim 3 will test whether FFAR4 or ciliary loss is an important driver of diabetic disease progression, setting up critical tests of FFAR4 and other GPCRs for normalizing adipogenesis and improving insulin secretion in aging, diabetic patients.
Terms: <3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><Acceleration><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Adipocytes><Adipose Cell><Adipose tissue><Aging><Agonist><Antibodies><Antidiabetic Hormone><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B9 endocrine pancreas><BODIPY><BUdR><Beta Cell><Beta Cell Neoplasm><Beta Cell Neoplasm of the Pancreas><Beta Cell Tumor of the Pancreas><Bioassay><Biological Assay><Blood Vessels><Body Tissues><BrdU><Bromodeoxyuridine><Bromouracil Deoxyriboside><Broxuridine><CD140a Antigens><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Calcium><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cilia><Coloring Agents><Cyclic AMP><D-Glucose><Dextrose><Diabetes Mellitus><Differences between sexes><Differs between sexes><Dinoprostone><Disease Progression><Dyes><Early identification><Endocrine Gland Secretion><Endocrine Pancreas><Event><FFAR1><FFAR1 gene><Fat Cells><Fat Droplet><Fats><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Formulation><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><GLP-1><GPCR><GPCR Signaling><Gender><Generalized Growth><Genes><Genetic><Glucagon><Glucose><Glucose Intolerance><Glukagon><Growth><Growth Agents><Growth Factor><Growth Substances><HG-Factor><High Fat Diet><Histologic><Histologically><Hormones><Human><Human Genetics><Humulin R><Hyperglycemic-Glycogenolytic Factor><Hypertrophy><Hypoxia><Hypoxic><IGF1><IGF1 gene><IGFI><Immune Cell Activation><In Vitro><Inflammation><Inflammatory><Insulin><Insulin Cell><Insulin Resistance><Insulin Secreting Cell><Insulin-Producing Neoplasm of the Islet Cells><Insulin-Producing Tumor of the Islet Cells><Insuloma><Intermediary Metabolism><Intracellular Communication and Signaling><Islands of Langerhans><Islets of Langerhans><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Ligands><Link><Lipid Inclusion><Lipids><Lipocytes><Mature Lipocyte><Mature fat cell><Mesenchymal><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nesidioblasts><Novolin R><Null Mouse><Nutritional><Obesity><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega3><Organism><Oxygen Deficiency><PDGF alpha Receptor><PDGF receptor α><PDGF-R-alpha><PDGFR-α><PDGFRα><PGE Receptors><PGE2><PGE2 Receptors><PGE2 alpha><PGE2alpha><Pancreatic Beta Cell Insulin Producing Neoplasm><Pancreatic Beta Cell Insulin Producing Tumor><Pancreatic Beta Cell Tumor><Pancreatic Islets><Pancreatic beta Cell><Pancreatic β-Cell><Pars endocrina pancreatis><Pathway interactions><Patients><Pharmacology><Phosphodiesterases><Platelet-Derived Growth Factor Receptor Alpha Polypeptide><Platelet-Derived Growth Factor alpha Receptor><Production><Progenitor Cells><Prostaglandin E Receptor><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandins><Prostanoids><Proteins Growth Factors><Proteomics><Publishing><Receptor Protein><Regular Insulin><Regulation><Reporter><S Period><S phase><Saturated Fatty Acids><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure of beta Cell of islet><Synthesis Period><Synthesis Phase><System><Tamoxifen><Testing><Therapeutic Hormone><Tissue Expansion><Tissue Growth><Tissues><Translation Initiation><Translations><adenosine 3'5' monophosphate><adipocyte development><adipocyte differentiation><adipogenesis><adipose><adiposity><adult progenitor><adult stem cell><beta-Cell Adenoma><beta-Cell Tumor><biological signal transduction><cAMP><cell type><clustered regularly interspaced short palindromic repeats screen><corpulence><diabetes><diabetic><diabetic patient><dietary><differentiation protocol><feeding><gene testing><gene-based testing><genetic testing><genome scale><genome wide screen><genome-wide><genomewide><glucagon-like peptide 1><human disease><immune activation><improved><insulin resistant><insulin secretion><insulin signaling><insulin tolerance><insulinoma><islet><islet progenitor><lipid biosynthesis><lipogenesis><living system><mouse model><multiomics><multiple omics><murine model><n-3 Fatty Acids><nutritious><obese patients><omega-3><ontogeny><pancreas beta cell><pancreas β cell><pancreatic b-cell><panomics><pathway><patients with obesity><phosphoric diester hydrolase><platelet-derived growth factor receptor α><progenitor cell population><progenitor population><programs><receptor><sensor><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><somatic progenitor><somatic stem cell><stem and progenitor cell population><stem cell population><stem cells><synergism><therapeutically effective><trafficking><translation><vascular><white adipose tissue><yellow adipose tissue><β-cell><β-cells><βCell><ω-3 fatty acids>