HSP72 protects against obesity-induced insulin resistance
Chung, J and Nguyen, A-K and Henstridge, DC and Holmes, AG and Chan, MHS and Mesa, JL and Lancaster, GI and Southgate, RJ and Bruce, CR and Duffy, SJ and Horvath, I and Mestril, R and Watt, MJ and Hooper, PL and Kingwell, BA and Vigh, L and Hevener, A and Febbraio, MA, HSP72 protects against obesity-induced insulin resistance, Proceedings of the National Academy of Sciences of the United States of America, 105, (5) pp. 1739-1744. ISSN 0027-8424 (2008) [Refereed Article]
Copyright 2008 by The National Academy of Sciences of the USA
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 signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of κB kinase, and tumor necrosis factor-α, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.
inflammation, JNK, metabolic disorders, stress proteins, type 2 diabetes, heat shock protein 72, I kappa B kinase, stress activated protein kinase, tumor necrosis factor alpha, adiponectin, insulin, oxime