Exercise, heat shock proteins and insulin resistance

Abstract

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Keywords: aerobic capacity; heat treatment; inflammation; mitochondria; skeletal muscle.

Figure 1.

Targeting heat shock proteins in the prevention of insulin resistance. Schematic depicting the timeline of metabolic disease from insulin resistance to type 2 diabetes. Insulin resistance can persist for 10–12 years prior to clinical diagnosis of type 2 diabetes, a time period that represents an increased risk for cardiovascular disease, obesity and type 2 diabetes. During insulin resistance, insulin secretion (red line) from pancreatic beta cells increases in an effort to maintain blood glucose (blue line). Insulin sensitivity declines (yellow line) resulting in a gradual increase in blood glucose and the development of type 2 diabetes. Insulin resistance represents a window of time when progression towards more severe metabolic disease can be prevented by lifestyle interventions like diet and exercise. HSPs are robustly induced by exercise, and HSP72 mRNA and protein expression are significantly reduced in the skeletal muscle of type 2 diabetic patients. However, very little is known about HSP expression patterns and regulation during insulin resistance. We hypothesize that HSP72 expression, in particular, may demonstrate an inverted parabolic relationship wherein initial increases in HSP72 combat metabolic dysfunction, but expression levels eventually peak and decline with disease severity and time spent under metabolic strain (solid green line). Exercise and heat treatment represent potential targeted therapies that could maintain and even increase HSP expression to prevent metabolic disease (dashed green line).