Role of chemical chaperones in treating obesity related metabolic diseases (#8)
It is well known that when proteins aggregate, illnesses such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis arise (1). Activation of chaperone proteins can suppress diseases associated with protein misfolding (2). However, the role of chaperone proteins in the treatment of metabolic diseases such as type 2 diabetes (T2D) has been relatively understudied. We (3-5) and others (6) have been studying the role of molecular chaperone proteins in the treatment of T2D. Specifically, we have been studying the role of heat shock protein 72 (HSP72). We have identified an essential role of HSP72 in preventing obesity-induced insulin resistance, using both loss of function and gain of function genetic mouse models and, via the use of small molecule activators of HSP72 currently in human clinical trials for T2D. This lecture will discuss these data and evaluate the clinical utility for molecules that activate molecular chaperone proteins in the treatment of obesity-related diseases.
1. Hartl, F.U., et al. Molecular chaperones in protein folding and proteostasis. Nature 475, 324-332 (2011).
2. Hoshino, T., et al. Suppression of Alzheimer's disease-related phenotypes by expression of heat shock protein 70 in mice. J Neurosci. 31:5225-5234 (2011).
3. Chung, J., et al. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105, 1739-1744 (2008).
4. Bruce, C.R., et al. Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52, 2338-2345 (2003).
5. Crul T,. et al. Hydroximic acid derivatives: Pleiotropic HSP co-inducers restoring homeostasis and robustness. Curr Pharm Des 19: 309-346 (2013).
6. Ozcan, U., et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137-1140 (2006).