Mechanisms and significance of adiponectin's metabolic actions in muscle

Adiponectin is an important regulator of insulin sensitivity and glucose metabolism in skeletal muscle. This thesis examined: Study 1 - the effects of adiponectin and adipose-derived factors on glucose uptake into L6 skeletal muscle cells, Study 2 - the effect of adipocyte coculture or adipocyte-conditioned media (ACM) treatment from healthy and diabetic rat adipocytes on signaling and glucose transport into L6 cells, Study 3 - the role of actin cytoskeleton in regulating adiponectin and ACM induced glucose transport into L6 cells, and Study 4 - the in vivo significance of skeletal muscle produced adiponectin.;Study 2: The stimulation of glucose transport and activation of AMPK and insulin receptor substrate (IRS) and Akt/protein kinase B in L6 cells by coculture or ACM was reduced when diabetic rat adipocytes were used compared to wild-type adipocytes. Analysis of adipokine secretion revealed a reduction in multimeric adiponectin in serum and ACM from diabetic rats.;Study 3: Globular adiponectin (gAd) and ACM induced actin cytoskeleton remodeling in L6 cells which is essential for the regulation of glucose transport as disassembly of the actin cytoskeleton by cytochalasin D (CD) abolished glucose transport. AMPK activation by gAd was dependent on the actin cytoskeleton as CD inhibited AMPK phosphorylation. Globular adiponectin stimulated the phosphorylation of cofilin but no activation of small Rho GTPase Rac1 was observed.;Study 4: The functional effects of skeletal muscle produced adiponectin on metabolism in chow fed and diet-induced obese mice was examined by utilizing Ultrasound Targeted Microbubble Destruction Technology to overexpress adiponectin in mouse skeletal muscle. An apparent improvement of insulin signaling and sensitivity was observed in obese mice overexpressing skeletal muscle adiponectin. These results suggest a beneficial effect of skeletal muscle produced adiponectin on glucose metabolism.;Study 1: Adipocyte coculture or ACM induced acute and chronic stimulation of glucose uptake into L6 cells via activation of 5' AMP-activated protein kinase (AMPK). Adiponectin was established as the primary mediator of these effects as adiponectin neutralization resulted in blunted glucose transport.;In summary, my studies demonstrated that multimeric adiponectin derived from primary adipocytes, skeletal muscle and recombinant sources can enhance skeletal muscle glucose metabolism.