Abstract
Aims/HypothesisHigh fat diet (HFD)-induced insulin resistance (IR) is partially characterized by reduced skeletal muscle mitochondrial function and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α) expression. Our previous study showed that a high dose of the bioflavonoid quercetin exacerbated HFD-induced IR; yet, others have demonstrated that quercetin improves insulin sensitivity. The aim of this study was to investigate whether differing doses of quercetin act in a time-dependent manner to attenuate HFD-induced IR in association with improved skeletal muscle mitochondrial function and PGC1α expression.MethodsC57BL/6J mice were fed HFD for 3 or 8 wks, with or without a low (50 ug/day; HF+50Q) or high (600 ug/day, HF+600Q) dose of quercetin. Whole body and metabolic phenotypes and insulin sensitivity were assessed. Skeletal muscle metabolomic analysis of acylcarnitines and PGC1α mRNA expression via qRT-PCR were measured.ResultsQuercetin at 50 ug/day for 8 wk attenuated HFD-induced increases in fat mass, body weight and IR and increased PGC1α expression, whereas 600 ug/day of quercetin exacerbated fat mass accumulation without altering body weight, IR or PGC1α. PGC1α expression correlated with acylcarnitine levels similarly in HF and HF+600Q; these correlations were not present in HF+50Q. At both time points, energy expenditure increased in HF+50Q and decreased in HF+600Q, independent of PGC1α and IR.Conclusions/InterpretationChronic dietary quercetin supplementation at low but not higher dose ameliorates the development of diet-induced IR while increasing PGC1α expression in muscle, suggesting that skeletal muscle may be an important target for the insulin-sensitizing effects of a low dose of quercetin.
Highlights
Reduced skeletal muscle mitochondrial function may play an integral role in the onset of insulin resistance (IR) during dietinduced obesity [1,2,3,4,5]
By week 8 of the study, high fat (HF) exhibited a 10.11 g increase in body weight (BW) compared to week 0, HF+50Q increased by 7.45 g and HF+600Q increased by 9.71 g (Fig. 1B)
BW was not significantly different between HF and HF+600Q, there was a significant increase in fat mass between the two groups, which converged by the end of the 8 wk period (Fig. 1D)
Summary
Reduced skeletal muscle mitochondrial function may play an integral role in the onset of insulin resistance (IR) during dietinduced obesity [1,2,3,4,5]. Integration of dietary fat intake and alterations in mitochondrial biogenesis and function are partially mediated by peroxisome proliferator receptor gamma coactivator 1 alpha (PGC1a) expression [6,7,8]. PGC1a plays an important role in fiber type switching to oxidative type 1 fibers [12] and in promoting mitochondrial biogenesis [11]. The downregulation of PGC1a expression and mitochondrial function in response to diet makes PGC1a an ideal target for the treatment of obesity and type 2 diabetes
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