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Principal Investigator: Samuel Klein
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $59,881
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Obesity is associated with an increased risk of serious metabolic abnormalities, such as type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). Data obtained from studies conducted in humans and rodents have suggested that “metabolic inflexibility” is critically involved in the pathophysiology of such metabolic abnormalities. The mechanism(s) responsible for obesity-induced metabolic inflexibility is not clear but could involve altered metabolic activity in white adipose tissue (WAT). In the current funding cycle of this grant, we have focused on studying adipose tissue NAD+ biology and conducted a series of studies that demonstrate the causal relationship between defective WAT NAD+ metabolism and metabolic inflexibility. We found: 1) loss of NAMPT, a key NAD+ biosynthetic enzyme, impairs cellular insulin signaling, mitochondrial function, and adrenergic-stimulated lipolytic activity in WAT; 2) adipocyte-specific Nampt knockout (ANKO) mice have multi-organ (skeletal muscle, liver, WAT) insulin resistance, hypoadiponectinemia, impaired adaptive thermogenesis and whole-body energy metabolism, and impaired fuel selection to hypercaloric and hypocaloric challenges; 3) a novel molecular link between NAD+ metabolism and Caveolin-1 (CAV1), a key regulator of whole-body metabolic flexibility; 4) dietary restriction and exercise, well-known enhancers of metabolic flexibility, stimulate NAMPT-mediated NAD+ biosynthesis in WAT; and 5) consistent with our rodent data, people with obesity have decreases in WAT NAMPT expression and NAD+ concentration. Based on these findings, this renewal application will test the hypotheses that NAMPT-mediated NAD+ biosynthesis regulates CAV1 and mitochondrial function in WAT, key effectors of metabolic flexibility and glucose metabolism, and that defective WAT NAD+ metabolism is a novel mechanism and therapeutic target for obesity-induced metabolic inflexibility. In Aim 1, we propose to generate two novel mouse models, mice overexpressing NAMPT selectively in visceral WAT (using the novel AAV system) and tamoxifen-inducible ANKO (iANKO) mice, and evaluate metabolic responses to high-fat diet feeding and lifestyle modification (dietary restriction, exercise). In Aim 2, we propose to use in vitro systems and explore four mechanisms (lysine acetylation of CAV1, PPARG, sirtuins, and redox metabolism) that link NAD+ metabolism with CAV1 and mitochondrial function. Finally, in Aim 3, we propose to determine the potential clinical relevance of the studies we conducted in the mouse model (Aim 1) and cell culture systems (Aim 2). Specifically, we will evaluate the effects of two potential “NAD+ enhancers”, namely lifestyle modification (low- calorie diet ± supervised exercise training) and nicotinamide mononucleotide (NMN) supplementation (250 mg/day, 8 weeks), on WAT NAD+ metabolism, CAV1, and mitochondrial biology in overweight people. The anticipated results obtained from this proposal will provide novel insight into the importance of adipose tissue NAD+ biology in regulating metabolic flexibility and glucose metabolism.
Terms: <22kD Caveolae Protein><Acetylation><Adeno-Associated Viruses><Adipocytes><Adipose Cell><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Adult-Onset Diabetes Mellitus><Anabolism><Biology><Biopsy Sample><Biopsy Specimen><Blood Sample><Blood specimen><Body Tissues><Body Weight decreased><Calories><Caveolin 1, Caveolae Protein, 22kD><Cell Culture System><Clinical><Coenzymes><Data><Dependoparvovirus><Dependovirus><Diet><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Dysfunction><Energy Expenditure><Energy Metabolism><Enhancers><Enzyme Cofactors><Enzyme Gene><Enzymes><Exercise><Fat Cells><Fatty Tissue><Foundations><Functional disorder><Funding><GEM model><GEMM model><Genetic><Genetically Engineered Mouse><Grant><HUMPPARG><Heat Production><High Fat Diet><Human><Impairment><In Vitro><Insulin Resistance><Intermediary Metabolism><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><L-Lysine><Life Style Modification><Link><Lipocytes><Liver><Lysine><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Murine><Mus><NAFLD><NIDDM><NMN pyrophosphorylase><NR1C3><Nadide><Nicotinamide Mononucleotide><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Obese Mice><Obesity><Organ><Over weight><Overweight><Oxidation-Reduction><PPARG><PPARG gene><PPARG1><PPARG2><Persons><Physiologic><Physiological><Physiopathology><Placebos><Prediabetes><Prediabetes syndrome><Prediabetic State><Redox><Risk><Rodent><Rodentia><Rodents Mammals><Series><Sham Treatment><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuins><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Supplementation><System><T2 DM><T2D><T2DM><Tamoxifen><Testing><Thermogenesis><Tissues><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><VIP21><VIP21 protein><Visceral><Voluntary Muscle><Weight Loss><Weight Reduction><adeno associated virus group><adipose><adiposity><adult onset diabetes><biosynthesis><body weight loss><caveolin 1><clinical relevance><clinically relevant><coenzyme analog><corpulence><diet restriction><dietary restriction><diets><exercise training><feeding><flexibility><flexible><genetically engineered mouse model><genetically engineered murine model><glucose metabolism><hepatic body system><hepatic organ system><improved><indexing><insight><insulin resistant><insulin sensitivity><insulin signaling><insulin tolerance><ketosis resistant diabetes><lifestyle modification><maturity onset diabetes><mitochondrial><mouse model><murine model><nicotinamide phosphoribosyltransferase><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><ob/ob mouse><obesity intervention><obesity therapy><obesity treatment><overexpress><overexpression><oxidation reduction reaction><pathophysiology><pharmacologic><pre-diabetes><pre-diabetic><prediabetic><response><restricted diet><sham therapy><therapeutic target><type 2 DM><type II DM><type two diabetes><vesicular integral membrane protein 21 kDa><white adipose tissue><wt-loss><yellow adipose tissue>