Obesity and its associated metabolic diseases are one of the greatest public health challenges in the United States. Insulin resistance is a primary contributor to this increase in metabolic disease with obesity and is proposed to arise secondary to an inflammatory response caused by infiltration of adipose tissue (AT) with macrophages and increased pro-inflammatory cytokine production. Surprisingly, however, the cellular signals within AT that initiate and propagate the inflammatory phenotype in response to nutrient excess are largely unknown, highlighting a significant gap in knowledge. Phosphoinosital 3-kinase (PI3K) regulates key insulin, cytokine, and growth signaling pathways, and is thus a strong candidate for linking cellular insulin resistance with the inflammatory response. We recently found a 2-4-fold increase in the PI3K p55? and p50? regulatory subunits in parallel with reduced insulin sensitivity in adipocytes from high-fat diet (HFD)-induced obese mice. Blocking HFD-induced increase in p55? and p50? through global heterozygous deletion of Pik3r1, the gene that encodes the regulatory subunits, reduced AT macrophage infiltration and significantly improved adipocyte, skeletal muscle and systemic insulin sensitivity in obese mice. Studies by our group have identify sirtuin 1 (SIRT1) and signal transducer and activator of transcription 3 (STAT3) as key regulators of p50? and p55? expression and subsequent PI3K activity in muscle with nutrient restriction, highlighting a potential universal link between insulin sensitivity and cellular energy status. We hypothesize that nutrient excess increases adipocyte p55? and p50? abundance to, 1) inhibit insulin-stimulated PI3K signaling, further suppressing nutrient uptake and, 2) promote PI3K-mediate NF?B activation, thereby stimulating cytokine production and macrophage recruitment. In contrast to the current paradigm, we predict that insulin resistance itself, through PI3K signaling promotes the inflammatory response, rather than inflammation causing insulin resistance. To address this hypothesis, we will use an integrative approach that combines whole animal physiology with cell and molecular techniques. Specifically, AIM1 will use transgenic mouse models with adipocyte-specific knockdown or over-expression of p55? and p50? to investigate whether increased adipocyte p55? and p50? abundance is necessary and sufficient to stimulate macrophage recruitment after acute or chronic HFD feeding.
In AIM2, we will test in vitro whether increased adipocyte p55? and p50? alters cytokine secretion through up-regulation of NF?B signaling to promote macrophage chemotaxis and/or inhibition of insulin suppression of lipolysis.
In AIM3, we will use transgenic mouse models to determine in vivo if the HFD-induced increase in AT p55? and p50? is downstream of a SIRT1-STAT3 axis. Considering the integral role of PI3K in metabolic disease and cancer research, these studies will provide unique new resources for PI3K research, will broaden our understanding of PI3K regulation and will facilitate the development of more focused approaches for targeting PI3K, which has the potential to treat metabolic, and ultimately impact human health.
Insulin resistance in obesity significantly increases an individual's risk for developing metabolic diseases such as type 2 diabetes and cardiovascular disease. These studies will determine the cellular systems that contribute to the chronic inflammatory response and insulin resistance in obesity, with particular focus on PI3K. Knowledge gathered will allow the design of novel therapeutics to improve metabolic health in obesity.
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