Retinol supplementation prevents weight gain and improves glucose homeostasis by regulating mitochondrial bioenergetics in high-fat diet fed mice

Kuwait has one of the highest rates of diabetes and obesity (1) . Retinol plays a crucial role in metabolic regulations of lipids and glucose, and in mitochondrial bioenergetics (1-3) . We hypothesized that retinol supplementation would prevent obesity and insulin resistance in mice fed a high-fat diet (HFD). We investigated the effect of retinol supplementation on weight changes and glucose homeostasis. Mice (C57; male and female) were supplemented either for 4 weeks (HFD-R4) or 8 weeks (HFD-R8), while being fed HFD for 8 weeks. Two control groups were given either an HFD or a low-fat diet (LFD). At the end of the trial, animals were weighed, and blood and tissues were collected for various biomarkers and proteomic analysis. Data are expressed as mean (SD) of 5 replicates in each group. Group comparisons were performed with ANOVA with significance level at p<0.05. No effect of retinol on body weight was seen in female mice. In male mice, the HFD-R8 group gained significantly less weight. Mean body weights were 29.6g, 41.3g, 41.2g, and 32.8g for control-LFD, Control-HFD, HFD-R4 and HFD-R8 groups, respectively. HFD-R8 grouphad better glucose control, and significantly lower levels of plasma leptin and insulin compared to all other groups. Proteomic analyses of liver samples revealed upregulation of 169 proteins in the HFD-R8 group (abundance ratio of ≥2) and downregulation of 143 proteins (abundance ratio of ≤0.5). Several of the upregulated proteins are involved in energy metabolism including glycogen phosphorylase, fatty acid-binding protein, complex I assembly factor TIMMDC1, pyruvate dehydrogenase kinase isozyme 3, cytochrome b, pyruvate carrier 2, very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 2, NADH- ubiquinone oxidoreductase chain 5, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7, ribulose-phosphate 3-epimerase, beta-enolase, glycerate kinase, Acyl-CoA (8-3)-desaturase, retinol dehydrogenase ADH4 and electron transfer flavoprotein regulatory factor 1. Notable down-regulated proteins included phosphorylase b kinase regulatory subunit beta, acyl-CoA desaturase 3, cytochrome c oxidase assembly protein COX16 homolog, hexokinase-1, glycerol-3-phosphate acyltransferase 4, pyruvate dehydrogenase kinase isozyme 2, and acylcarnitine hydrolase. These findings indicate that retinol modulates weight gain and glucose homeostasis by regulating mitochondrial bioenergetics. This study highlights the potential of retinol supplementation in obesity prevention and warrants further studies in humans.