Alkyl resorcinol protects against obesity-related metabolic disorder with mitochondrial activation by PGC-1α deacetylation

Abstract

The deacetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) by the activation of mammalian sirtuins (SIRTs) promotes mitochondrial function and metabolic homeostasis. We previously demonstrated that alkylresorcinols (ARs) from rye wheat raised the Vmax of recombinant SIRT1 for NAD+ and extended the lifespan of the fruit fly Drosophila melanogaster. Olivetol (1,3-Dihydroxy-5-pentylbenzene), the smallest alkyl chain AR from lichen, also raised the Vmax of recombinant SIRT1. We hypothesized that the specific deacetylation of PGC-1α would: (i) be enhanced by increasing the rate of the enzyme-catalyzed reaction of SIRT1, and (ii) affect mitochondrial function and obesity-related metabolic disorders. We investigated the effect of ARs on obesity in mice fed a high-fat diet and in humans. The weight of the olivetol-high-fat diet (HFD) mice was significantly suppressed compared to the control-HFD group. The human subjects’ BMI was significantly lower in both the first and second halves of the 40-day test period compared to the placebo group. Compared to the control-HFD data, the amount of acetylated PGC-1α in the skeletal muscle of the olivetol-HFD mice was significantly decreased and the number of mitochondria in their brown adipose tissue (BAT) was significantly increased. In a supplementary experiment, the median lifespan of Drosophila melanogaster fed the olivetol-HFD was significantly extended by up to 113% in males and 109% in females versus that in the D. melanogaster fed a normal diet. The AR effects were thus associated with an induction of genes for lipid metabolism and were largely explained by PGC-1α deacetylation.