Heat shock protein 72 regulates hepatic lipid accumulation.

Induction of the chaperone heat shock protein 72 (HSP72) through heat treatment (HT), exercise, or overexpression improves glucose tolerance and mitochondrial function in skeletal muscle. Less is known about HSP72 function in the liver where lipid accumulation can result in insulin resistance and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was 1) to determine whether weekly in vivo HT induces hepatic HSP72 and improves glucose tolerance in rats fed a high-fat diet (HFD) and 2) to determine the ability of HSP72 to protect against lipid accumulation and mitochondrial dysfunction in primary hepatocytes. Male Wistar rats were fed an HFD for 15 wk and were given weekly HT (41°C, 20 min) or sham treatments (37°C, 20 min) for the final 7 wk. Glucose tolerance and insulin sensitivity were assessed, along with HSP72 induction and triglyceride storage, in the skeletal muscle and liver. The effect of an acute loss of HSP72 in primary hepatocytes was examined via siRNA. Weekly in vivo HT improved glucose tolerance, elevated muscle and hepatic HSP72 protein content, and reduced muscle triglyceride storage. In primary hepatocytes, mitochondrial morphology was changed, and fatty acid oxidation was reduced in small interfering HSP72 (siHSP72)-treated hepatocytes. Lipid accumulation following palmitate treatment was increased in siHSP72-treated hepatocytes. These data suggest that HT may improve systemic metabolism via induction of hepatic HSP72. Additionally, acute loss of HSP72 in primary hepatocytes impacts mitochondrial health as well as fat oxidation and storage. These findings suggest therapies targeting HSP72 in the liver may prevent NAFLD.

Exercise, heat shock proteins and insulin resistance.

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'.

Effect of APOE ε4 Genotype on Metabolic Biomarkers in Aging and Alzheimer's Disease.

Alzheimer's disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n = 213 nondemented (ND), n = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p = 0.04) and in APOE4 noncarriers versus carriers (p < 0.01). This was driven by increased fasting insulin in AD versus ND (p < 0.01) and in APOE4 non-carriers versus carriers (p = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.

Deficiency in the Heat Stress Response Could Underlie Susceptibility to Metabolic Disease.

Heat treatment (HT) effectively prevents insulin resistance and glucose intolerance in rats fed a high-fat diet (HFD). The positive metabolic actions of heat shock protein 72 (HSP72), which include increased oxidative capacity and enhanced mitochondrial function, underlie the protective effects of HT. The purpose of this study was to test the ability of HSP72 induction to mitigate the effects of consumption of a short-term 3-day HFD in rats selectively bred to be low-capacity runners (LCRs) and high-capacity runners (HCRs)-selective breeding that results in disparate differences in intrinsic aerobic capacity. HCR and LCR rats were fed a chow or HFD for 3 days and received a single in vivo HT (41°C, for 20 min) or sham treatment (ST). Blood, skeletal muscles, liver, and adipose tissues were harvested 24 h after HT/ST. HT decreased blood glucose levels, adipocyte size, and triglyceride accumulation in liver and muscle and restored insulin sensitivity in glycolytic muscles from LCR rats. As expected, HCR rats were protected from the HFD. Importantly, HSP72 induction was decreased in LCR rats after only 3 days of eating the HFD. Deficiency in the highly conserved stress response mediated by HSPs could underlie susceptibility to metabolic disease with low aerobic capacity.

Impaired fasting glucose is associated with increased regional cerebral amyloid.

The Alzheimer's disease risk gene apolipoprotein E epsilon 4 (APOE ε4) is associated with increased cerebral amyloid. Although impaired glucose metabolism is linked to Alzheimer's disease risk, the relationship between impaired glycemia and cerebral amyloid is unclear. To investigate the independent effects of APOE ε4 and impaired glycemia on cerebral amyloid, we stratified nondemented subjects (n = 73) into 4 groups: normal glucose, APOE ε4 noncarrier (control [CNT]; n = 31), normal glucose, APOE ε4 carrier (E4 only; n = 14) impaired glycemia, APOE ε4 noncarrier (IG only; n = 18), and impaired glycemia, APOE ε4 carrier (IG+E4; n = 10). Cerebral amyloid differed both globally (p = 0.023) and regionally; precuneus (p = 0.007), posterior cingulate (PCC; p = 0.020), superior parietal cortex (SPC; p = 0.029), anterior cingulate (p = 0.027), and frontal cortex (p = 0.018). Post hoc analyses revealed that E4 only subjects had increased cerebral amyloid versus CNT globally and regionally in the precuneus, PCC, SPC, anterior cingulate, and frontal cortex. In IG only subjects, increased cerebral amyloid compared with CNT was restricted to precuneus, PCC, and SPC. IG+E4 subjects exhibited higher cerebral amyloid only in the precuneus relative to CNT. These results indicate that impaired glycemia and APOE ε4 genotype are independent risk factors for regional cerebral amyloid deposition. However, APOE ε4 and impaired glycemia did not have an additive effect on cerebral amyloid.