Independent, but not co-supplementation, with nitrate and resveratrol improves glucose tolerance and reduces markers of cellular stress in high-fat-fed male mice

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 324; no. 3; p. R317
• Main Authors: Handy, Rachel M, DesOrmeaux, Geneviève J, Barbeau, Pierre-Andre, Frangos, Sara M, Holloway, Graham P
• Format: Journal Article
• Language: English
• Published: United States 01-03-2023
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Diet, High-Fat; Dietary Supplements; Glucose - metabolism; Lipids; Male; Mice; Nitrates - pharmacology; Resveratrol - pharmacology; Sirtuin 1 - metabolism; glucose homeostasis; metabolism; resveratrol; sodium nitrate; mitochondria
• ISSN: 1522-1490
• DOI: 10.1152/ajpregu.00196.2022

Independent supplementation with nitrate (NIT) and resveratrol (RSV) enriches various aspects of mitochondrial biology in key metabolic tissues. Although RSV is known to activate Sirt1 and initiate mitochondrial biogenesis, the metabolic benefits elicited by dietary nitrate appear to be dependent on 5'-adenosine monophosphate-activated protein kinase (AMPK)-mediated signaling events, a process also linked to the activation of Sirt1. Although the benefits of individual supplementation with these compounds have been characterized, it is unknown if co-supplementation may produce superior metabolic adaptations. Thus, we aimed to determine if treatment with combined +NIT and +RSV (+RN) could additively alter metabolic adaptations in the presence of a high-fat diet (HFD). Both +RSV and +NIT improved glucose tolerance compared with HFD (
< 0.05); however, this response was attenuated following combined +RN supplementation. Within skeletal muscle, all supplements increased mitochondrial ADP sensitivity compared with HFD (
< 0.05), without altering mitochondrial content. Although +RSV and +NIT decreased hepatic lipid deposition compared with HFD (
< 0.05), this effect was abolished with +RN, which aligned with significant reductions in Sirt1 protein content (
< 0.05) after combined treatment, in the absence of changes to mitochondrial content or function. Within epididymal white adipose tissue (eWAT), all supplements reduced crown-like structure accumulation compared with HFD (
< 0.0001) and mitochondrial reactive oxygen species (ROS) emission (
< 0.05), alongside reduced adipocyte cross-sectional area (CSA) (
< 0.05), with the greatest effect observed after +RN treatment (
= 0.0001). Although the present data suggest additive changes in adipose tissue metabolism after +RN treatment, concomitant impairments in hepatic lipid homeostasis appear to prevent improvements in whole body glucose homeostasis observed with independent treatment, which may be Sirt1 dependent.