Nitrate attenuates high fat diet‐induced glucose intolerance in association with reduced epididymal adipose tissue inflammation and mitochondrial reactive oxygen species emission

Abstract

Key points Dietary nitrate is a prominent therapeutic strategy to mitigate some metabolic deleterious effects related to obesity. Mitochondrial dysfunction is causally linked to adipose tissue inflammation and insulin resistance. Whole‐body glucose tolerance is prevented by nitrate independent of body weight and energy expenditure. Dietary nitrate reduces epididymal adipose tissue inflammation and mitochondrial reactive oxygen species emission while preserving insulin signalling. Metabolic beneficial effects of nitrate consumption are associated with improvements in mitochondrial redox balance in hypertrophic adipose tissue. Abstract Evidence has accumulated to indicate that dietary nitrate alters energy expenditure and the metabolic derangements associated with a high fat diet (HFD), but the mechanism(s) of action remain incompletely elucidated. Therefore, we aimed to determine if dietary nitrate (4 mm sodium nitrate via drinking water) could prevent HFD‐mediated glucose intolerance in association with improved mitochondrial bioenergetics within both white (WAT) and brown (BAT) adipose tissue in mice. HFD feeding caused glucose intolerance (P < 0.05) and increased body weight. As a result of higher body weight, energy expenditure increased proportionally. HFD‐fed mice displayed greater mitochondrial uncoupling and a twofold increase in uncoupling protein 1 content within BAT. Within epididymal white adipose tissue (eWAT), HFD increased cell size (i.e. hypertrophy), mitochondrial H2O2 emission, oxidative stress, c‐Jun N‐terminal kinase phosphorylation and leucocyte infiltration, and induced insulin resistance. Remarkably, dietary nitrate consumption attenuated and/or mitigated all these responses, including rendering mitochondria more coupled within BAT, and normalizing mitochondrial H2O2 emission and insulin‐mediated Akt‐Thr308 phosphorylation within eWAT. Intriguingly, the positive effects of dietary nitrate appear to be independent of eWAT mitochondrial respiratory capacity and content. Altogether, these data suggest that dietary nitrate attenuates the development of HFD‐induced insulin resistance in association with attenuating WAT inflammation and redox balance, independent of changes in either WAT or BAT mitochondrial respiratory capacity/content.

WAT do you NO? Addressing obesity‐related cardiometabolic dysfunction

“…Consistent with previous reports, Brunetta et al . (2020) found that HFD feeding impaired whole‐body glucose tolerance, which was attenuated by dietary nitrate supplementation (Kina‐Tanada et al . 2017).…”

“…Additional trials are needed to determine if the compelling preclinical data presented by Brunetta et al . (2020) can be translated to obese adults.…”

“…The findings by Brunetta et al . (2020) demonstrate that HFD‐induced obesity promotes glucose intolerance, which is mechanistically linked to white adipose tissue (WAT) dysfunction characterized by inflammation and mitochondrial dysfunction, including increased mitochondria‐derived reactive oxygen species production. These changes may be responsible, in part, for obesity‐related reductions in nitric oxide (NO) bioavailability, which is linked to impaired arterial function and increased cardiovascular disease (CVD) risk.…”

“…The preclinical studies presented by Brunetta et al . (2020) suggest that nitrate supplementation during HFD feeding may improve whole‐body glucose tolerance by reducing mitochondrial ROS production by WAT, as well as reducing WAT inflammation and preserving insulin signalling. Notably, the nitrate‐mediated effect on glucose tolerance and insulin signalling in the setting of HFD‐induced obesity occurred without influencing body weight.…”

“…Taken together, the findings from the study by Brunetta et al . (2020) have significant implications for future clinical studies aimed at reducing cardiometabolic dysfunction.…”