Adipose T cell microRNAs (miRs) regulate macrophage function during obesity

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ABSTRACT Over the past 20 years, the prevalence of obesity in the United States and worldwide has reached epidemic proportions. Obesity is a very powerful health determinant that facilitates the development and progression of several metabolic diseases, insulin resistance and chronic inflammation. High fat diet (HFD) consumption positively correlates with development of obesity. T cells infiltrate adipose tissue during the early development of obesity (prior to macrophage influx) and are strongly implicated in the initiation of inflammation associated with obesity. In both humans and mice, macrophage abundance increases in obese adipose tissue and can develop either M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. During obesity progression differential expression of microRNAs (miRs) by naive and activated T cells suggests their importance in T cell effector (Teff) functions. Further, it is well established that miRs extensively regulate adipocyte development and function. We noticed T cell homeostatic expansion and changes in macrophage abundance and phenotype in adipose tissue of HFD fed mice compared to those fed a normal diet (ND). Specifically, our preliminary data indicates that HFD downregulates adipose resident T cell miRs-10a, -125b and -1247 and mimics miRs' in-vivo reversal of the expression of metabolic markers associated with obesity and modulates macrophage abundance. Based on strong rigor and preliminary data, our central hypothesis is that T cell miRs-10a, -125b and 1247 are essential for regulating crosstalk between adipocytes, T cells and macrophages during diet-induced obesity. To support this premise, we will test whether adipose T cell miRs play a crucial role in diet-induced obesity (DIO) (Aim 1); identify the mechanisms by which T cell miRs are downregulated in DIO (Aim 2); determine whether adipose T cell miRs mediate macrophage function in DIO (Aim 3). For the first time, we will explore how resident adipose tissue-derived T cell miRs alter metabolic function and obesity. Testing this hypothesis will provide an enhanced understanding on interactions between T cell miRs, T cell expansion, and macrophage and adipocyte function in the adipose tissue microenvironment that may allow for effective prevention and treatment options for obesity and metabolic dysfunction.