Effect of Blueberry Supplementation on a Diet-Induced Rat Model of Prediabetes-Focus on Hepatic Lipid Deposition, Endoplasmic Stress Response and Autophagy.

Blueberries, red fruits enriched in polyphenols and fibers, are envisaged as a promising nutraceutical intervention in a plethora of metabolic diseases. Prediabetes, an intermediate state between normal glucose tolerance and type 2 diabetes, fuels the development of complications, including hepatic steatosis. In previous work, we have demonstrated that blueberry juice (BJ) supplementation benefits glycemic control and lipid profile, which was accompanied by an amelioration of hepatic mitochondrial bioenergetics. The purpose of this study is to clarify the impact of long-term BJ nutraceutical intervention on cellular mechanisms that govern hepatic lipid homeostasis, namely autophagy and endoplasmic reticulum (ER) stress, in a rat model of prediabetes. Two groups of male Wistar rats, 8-weeks old, were fed a prediabetes-inducing high-fat diet (HFD) and one group was fed a control diet (CD). From the timepoint where the prediabetic phenotype was achieved (week 16) until the end of the study (week 24), one of the HFD-fed groups was daily orally supplemented with 25 g/kg body weight (BW) of BJ (HFD + BJ). BW, caloric intake, glucose tolerance and insulin sensitivity were monitored throughout the study. The serum and hepatic lipid contents were quantified. Liver and interscapular brown and epidydimal white adipose tissue depots (iBAT and eWAT) were collected for histological analysis and to assess thermogenesis, ER stress and autophagy markers. The gut microbiota composition and the short-chain fatty acids (SCFAs) content were determined in colon fecal samples. BJ supplementation positively impacted glycemic control but was unable to prevent obesity and adiposity. BJ-treated animals presented a reduction in fecal SCFAs, increased markers of arrested iBAT thermogenesis and energy expenditure, together with an aggravation of HFD-induced lipotoxicity and hepatic steatosis, which were accompanied by the inhibition of autophagy and ER stress responses in the liver. In conclusion, despite the improvement of glucose tolerance, BJ supplementation promoted a major impact on lipid management mechanisms at liver and AT levels in prediabetic animals, which might affect disease course.