Characterising nitric oxide-mediated metabolic benefits of low-dose ultraviolet radiation in the mouse: a focus on brown adipose tissue

Abstract

Aims/hypothesis Exposure to sunlight has the potential to suppress metabolic dysfunction and obesity. We previously demonstrated that regular exposure to low-doses of ultraviolet radiation (UVR) reduced weight gain and signs of diabetes in male mice fed a high-fat diet, in part via release of nitric oxide from skin. Here, we explore further mechanistic pathways through which lowdose UVR exerts these beneficial effects. Methods We fed mice with a luciferase-tagged Ucp1 gene (which encodes uncoupling protein-1 [UCP-1]), referred to here as the Ucp1 luciferase transgenic mouse ('Thermomouse') a high-fat diet and examined the effects of repeated exposure to low-dose UVR on weight gain and development of metabolic dysfunction as well as UCP-1-dependent thermogenesis in interscapular brown adipose tissue (iBAT). Results Repeated exposure to low-dose UVR suppressed the development of glucose intolerance and hepatic lipid accumulation via dermal release of nitric oxide while also reducing circulating IL-6 (compared with mice fed a high-fat diet only). Dietary nitrate supplementation did not mimic the effects of low-dose UVR. A single low dose of UVR increased UCP-1 expression (by more than twofold) in iBAT of mice fed a low-fat diet, 24 h after exposure. However, in mice fed a high-fat diet, there was no effect of UVR on UCP-1 expression in iBAT (compared with mock-treated mice) when measured at regular intervals over 12 weeks. More extensive circadian studies did not identify any substantial shifts in UCP-1 expression in mice exposed to low-dose UVR, although skin temperature at the interscapular site was reduced in UVR-exposed mice. The appearance of cells with a white adipocyte phenotype ('whitening') in iBAT induced by consuming the high-fat diet was suppressed by exposure to low-dose UVR in a nitric oxide-dependent fashion. Significant shifts in the expression of important core gene regulators of BAT function Gursimran K. Dhamrait and Kunjal Panchal contributed equally to this study.

Investigating the Potential for Ultraviolet Light to Modulate Morbidity and Mortality From COVID-19: A Narrative Review and Update

“…The same UV-driven mechanism may drive seasonal variation in development of diabetes and metabolic syndrome, and similar protective effects in people with sun-seeking behaviors (140). Our preclinical studies indicate that regular exposure to low doses (2-3 min, non-burning) of UV light inhibits metabolic dysfunction in mice fed a high fat diet, with beneficial effects on liver lipid levels, glucose tolerance, insulin sensitivity and adiposity (135,141,142). Glycemic control may be important to avoid long-term hospital stays, intensive care unit requirement and death from COVID-19 (143).…”

“…Some of the metabolic benefits of low dose UV light were mediated via the photo-mobilization of nitric oxide from skin (135,141,142); however, there is likely a role for other mediators including molecules affecting neuro-endocrine pathways (144), and those that mediate anti-inflammatory effects of UV radiation (142). It is likely that UV light has cardiometabolic benefits in both males and females, with body weight, fat mass and adiposity limited in both male and female mice exposed to low-dose UV light (135,141,142,145). Similarly, long-term treatment to narrowband UVB (n = 3,229) reduced the risk of cardiovascular and cerebrovascular events in both men and women with vitiligo (compared to those with few or no sessions: HR 0.64, 95% CI 0.52-0.78 for all events; n = 9,687) from Korea, although associations were more significant in females than males (146).…”

“…It is possible that the cascade of anti-inflammatory mediators produced in response to exposure to UV light (13), including nitric oxide (as above) and vitamin D, may act in concert to potentially prevent the COVID-19 cytokine storm and induced inflammation. Indeed, exposure to UV light (and such induced mediators) may reduce circulating pro-inflammatory cytokines linked to COVID-19 cytokine storm events, including interleukin-6 (IL-6) and c-reactive protein (101,127,142,150). Importantly, elevated IL-6 (>70 pg/ml) levels as well as other cytokines (after multivariate adjustment for sex, age, ethnicity, comorbidities) were associated with reduced survival (HR 2.47, p < 0.0001) of patients hospitalized for COVID-19 in New York (USA) (151).…”

Nitric oxide: To be or not to be an endocrine hormone?

“…Disrupted NO release from its photo‐reactive stores in the skin compromises blood pressure regulation and increases the risk of cardiovascular diseases . NO released from skin also mediates protective effects of UVA against high‐fat diet (HFD) (ie suppression of the brown adipose tissue whitening, steatotic and pro‐diabetic effects) . Lack of protective effects of dietary NO 3 and dermally applied NO donor in the absence of UVA irradiation in HFD‐treated mice may raise the hypothesis that each endocrine site of NO synthesis is responsible for specific endocrine action of NO in response to specific stimuli.…”

Low-dose UV radiation before running wheel access activates brown adipose tissue

“…glucose and lipid uptake, fatty acid biosynthesis), with the effects of exercise on mitochondrial activity not well described (Peres Valgas da Silva et al 2019). We have recently characterised the effects of low-dose UVR on metabolic functions in interscapular BAT (iBAT) (Dhamrait et al 2020), which lies beneath irradiated dorsal skin of mice exposed to UVR in our previous studies (Geldenhuys et al 2014, Teng et al 2019. Low-dose UVR curtailed whitening of iBAT through nitric oxide, while also modulating the expression of core gene regulators of BAT function through non-nitric oxide-dependent pathways (Dhamrait et al 2020).…”