The obesity epidemic and related metabolic syndrome now pose serious threats to public health. Studies have redefined the role of fat cells (adipocytes) as an active regulator of insulin-glucose metabolism: adipocytes can cause insulin resistance to glucose uptake or, on the contrary, enhance insulin sensitivity by secreting pro- or anti-inflammatory adipokines, respectively. Given this changeable role of adipocytes, elucidating adipocyte adaptation to extracellular environments may hold a great potential in developing therapeutic tools for metabolic disorders related to impaired insulin action. In addition to conventional diet condition-based approaches, with an increasing interest in the extent to which adipocytes can sense and respond to extracellular mechanical loading signals, this project will test novel adipocyte mechanotransduction for insulin sensitization. Based on key preliminary data supporting the proposed adipocyte load adaptation capability, this project will examine the extent to which mechanical stretch loading at a specific regimen (e.g., cyclic over static stretching) upregulates adipocyte insulin signaling activity (Specific Aim 1), and then will aim to uncover governing molecular mechanisms: anti-inflammatory adipokine based (Specific Aim 2) and focal adhesion mechanosensor based (Specific Aim 3). Further, the extent to which primary adipocytes from an obese phenotype and exercise model will respond differently to a mechanical loading signal will be tested (Specific Aim 4). It is expected that successful completion of these aims will lay a solid foundation for novel adipocyte mechanotransduction for insulin signaling regulation. Further, unveiling anti-inflammatory adipokine and an adipocyte mechanosensor that govern the stretchinduced enhancement of insulin signaling may illuminate potential therapeutic targets for insulin sensitivityor resistance-related metabolic diseases.