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Obesity and related metabolic disorders have reached global epidemic proportions in recent decades. Excess and hypertrophic adipose tissue has been implicated in the development of various pathological diseases and disorders including Type-2 diabetes mellitus (Type-2 DM). In addition to serving as energy storage for the body, evidence also suggests that adipose tissue behaves as an endocrine organ capable of secreting bioactive cytokines known as adipokines, which mediate insulin signaling pathways in various tissues. Physical exercise has been demonstrated to positively affect insulin signaling activities potentially through increasing the secretion of insulin sensitizing adipokines and/or decreasing the secretion of pro-inflammatory insulin desensitizing adipokines. However, cellular and molecular level mechanisms governing the exercise control of circulating adipokine secretion and its control of insulin signaling are not known. In this study, with the assumption that adipose tissue can be mechanically responsive (as is the case for well-known musculoskeletal tissues), we hypothesized that mechanical loading applied to the adipose tissue and its component cells, such as adipocytes, may play a role in the exercise control of insulin sensitivity. As a proof-ofconcept test, we applied cyclic stretch loading to the adipocyte model, differentiated adipocytes from 3T3-L1 preadipocytes, and evaluated stretch-induced activation of key insulin signaling molecules. Cells were differentiated on the stretchable membrane and then exposed to cyclic equibiaxial stretching using the Flexcell FX-5000 device at a frequency of 1 Hz and a strain of 5% for 2 h. It was observed that expressions of insulin receptor substrate-1 (IRS-1) and glucose transport-4 (GLUT4) were less influenced by stretch under the given conditions. On the other hand, interestingly, one of the key downstream insulin signaling molecules, protein kinase-B (PKB, or Akt) and its phosphorylation (pAkt) were significantly increased for cyclically stretched adipocytes relative to unstretched control. Moreover, cyclic stretch upregulated the phosphorylation of 5’-AMP-activated protein kinase (pAMPK). Combined data may suggest that mechanical stretch activates the insulin signaling pathway downstream of IRS-1, and possibly by the phosphorylation of Akt through AMPK activation. Since it is known that adipokines such as leptin and adiponectin can instigate their insulin signaling sensitizing effect via AMPK and Akt, we propose a mechanism that mechanical stretching of adipocytes may induce the secretion of insulin sensitizing adipokines like leptin and/or adiponectin, which in turn activates AMPK and Akt phosphorylation and, ultimately, improves insulin signaling in the adipose tissue. Advisor: Jung Yul Lim