Chaperoning to the metabolic party: The emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes.
BACKGROUND
From their initial, accidental discovery 50 years ago, the highly conserved Heat Shock Proteins (HSPs) continue to exhibit fundamental roles in the protection of cell integrity. Meanwhile, in the midst of an obesity epidemic, research demonstrates a key involvement of low grade inflammation, and mitochondrial dysfunction amongst other mechanisms, in the pathology of insulin resistance and type 2 diabetes mellitus (T2DM). In particular, tumor necrosis factor alpha (TNFα), endoplasmic reticulum (ER) and oxidative stress all appear to be associated with obesity and stimulate inflammatory kinases such as c jun amino terminal kinase (JNK), inhibitor of NF-κβ kinase (IKK) and protein kinase C (PKC) which in turn, inhibit insulin signaling. Mitochondrial dysfunction in skeletal muscle has also been proposed to be prominent in the pathogenesis of T2DM either by reducing the ability to oxidize fatty acids, leading to the accumulation of deleterious lipid species in peripheral tissues such as skeletal muscle and liver, or by altering the cellular redox state. Since HSPs act as molecular chaperones and demonstrate crucial protective functions in stressed cells, we and others have postulated that the manipulation of HSP expression in metabolically relevant tissues represents a therapeutic avenue for obesity-induced insulin resistance.


METHODS
This review summarizes the literature from both animal and human studies, that has examined how HSPs, particularly the inducible HSP, Heat Shock Protein 72 (Hsp72) alters glucose homeostasis and the possible approaches to modulating Hsp72 expression. A summation of the role of chemical chaperones in metabolic disorders is also included.


CONCLUSIONS
Targeted manipulation of Hsp72 or use of chemical chaperiones may have clinical utility in treating metabolic disorders such as insulin resistance and T2DM.
Cellular & Molecular Metabolism Laboratory, Division of Metabolism and Obesity, Baker IDI Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, Victoria 3004, Australia.
Darren C
DC
Henstridge
Cellular & Molecular Metabolism Laboratory, Division of Metabolism and Obesity, Baker IDI Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, Victoria 3004, Australia.
Martin
M
Whitham
Cellular & Molecular Metabolism Laboratory, Division of Metabolism and Obesity, Baker IDI Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, Victoria 3004, Australia.
Mark A
MA
Febbraio
Chemical chaperones; Hsp72; Inflammation; Insulin resistance; Mitochondria; Obesity; Oxidative capacity; Skeletal muscle; Type 2 diabetes