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.
Obesity is associated with ?metabolic inflexibility?, which is involved in the pathophysiology of obesity-induced metabolic abnormalities, such as type 2 diabetes and insulin resistance. The proposed studies aim to understand the mechanisms of obesity-induced metabolic flexibility and develop new obesity treatment by using genetically engineered mouse models, cell culture system, and human adipose tissue biopsy samples.
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