Patients with type 2 diabetes have reduced gene expression of Heat Shock Protein (HSP) 72 which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signalling proteins such as c-jun amino terminal kinase (JNK) can induce insulin resistance but HSP72 can block the induction of these molecules in vitro. Whether up-regulation of HSP72 can protect against insulin resistance is not known. In experiments reported in this thesis we show that HSP72 protects against insulin resistance and blocks the activation of JNK in vivo. We first show that mice that underwent weekly heat shock therapy to increase intramuscular HSP72 protein expression were protected from high fat diet (HFD)-induced hyperinsulinemia, hyperglycemia and glucose intolerance, factors associated with reduced JNK phosphorylation. To determine whether the elevation in intramuscular HSP72 expressio n and protection from insulin resistance are causally linked, we studied muscle specific HSP72 overexpression mice (HSP72+/+). Compared with wild-type mice, HSP72+/+ mice were protected from hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance when placed on a HFD, factors associated with a complete inhibition of HFD-induced JNK phosphorylation in skeletal muscle. Finally, we show that HSP72+/+ mice display greater mitochondrial enzyme activity in the liver, adipose tissue and skeletal muscle, corresponding to reduced plasma free fatty acid levels, white adipose tissue mass and alterations in circulating adipokines. These data identify HSP72 as being pivotal in protecting against obesity-induced insulin resistance possibly by blocking JNK and/or by up-regulation of mitochondrial oxidative capacity.
| Identifer | oai:union.ndltd.org:ADTP/210268 |
| Date | January 2008 |
| Creators | Chung, Jason, jason.chung@rmit.edu.au |
| Publisher | RMIT University. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.rmit.edu.au/help/disclaimer, Copyright Jason Chung |
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