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

In previous preclinical studies, low (non-burning) doses of UV radiation (UVR) limited weight gain and metabolic dysfunction in mice fed with a high-fat diet. Here, we explored the effects of low-dose UVR on physical activity and food intake and mechanistic pathways in interscapular brown adipose tissue (iBAT). Young adult C57Bl/6J male mice, housed as individuals, were fed a high-fat diet and exposed to low-dose UVR (sub-oedemal, 1 kJ/m2 UVB, twice-a-week) or 'mock' treatment, with or without running wheel access (2 h, for 'moderate' physical activity) immediately after phototherapy. There was no difference in distance run in mice exposed to UVR or mock-treated over 12 weeks of exposure to running wheels (P = 0.14). UVR (alone) did not significantly affect food intake, adiposity, or signs of glucose dysfunction. Access to running wheels increased food intake (after 10 weeks, P ≤ 0.02) and reduced gonadal white adipose tissue and iBAT mass (P ≤ 0.03). Body weight and hepatic steatosis were lowest in mice exposed to UVR with running wheel access. In the iBAT of mice exposed to UVR and running wheels, elevated Atgl, Cd36, Fasn, Igf1, Pparγ, and Ucp1 mRNAs and reduced CD11c on F4-80 + MHC class II+ macrophages were observed, while renal Sglt2 mRNA levels were increased, compared to high-fat diet alone (P ≤ 0.03). Blood levels of 25-hydroxyvitamin D were not increased by exposure to UVR and/or access to running wheels. In conclusion, when combined with physical activity, low-dose UVR may more effectively limit adiposity (specifically, body weight and hepatic steatosis) and modulate metabolic and immune pathways in iBAT.

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

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 low-dose 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 (Dio2, increased more than twofold), fatty acid transport (increased Fatp2 [also known as Slc27a2]), lipolysis (decreased Atgl [also known as Pnpla2]), lipogenesis (decreased Fasn) and inflammation (decreased Tnf), and proportions of macrophages (increased twofold) were observed in iBAT of mice exposed to low-dose UVR. These effects were independent of nitric oxide released from skin. CONCLUSIONS/INTERPRETATION: Our results suggest that non-burning (low-dose) UVR suppresses the BAT 'whitening', steatotic and pro-diabetic effects of consuming a high-fat diet through skin release of nitric oxide, with some metabolic and immune pathways in iBAT regulated by UVR independently of nitric oxide.

Regular exposure to non-burning ultraviolet radiation reduces signs of non-alcoholic fatty liver disease in mature adult mice fed a high fat diet: results of a pilot study.

OBJECTIVE: Obesity often emerges in middle age, increasing risk for metabolic disorders. Our previous preclinical experiments identified that chronic exposure to non-burning ultraviolet radiation, like that achieved through sun exposure, prevented weight gain and signs of metabolic dysfunction in young adult mice fed a high fat diet. Our objective was to perform a pilot study to estimate the effect size of ongoing exposure to sub-erythemal (non-burning, low dose) UVB (1 kJ/m2) radiation on measures of adiposity, food intake and physical activity in 'mature' adult C57Bl/6J male mice fed a high fat diet for 12 weeks. RESULTS: The severity of liver steatosis, fibrosis and inflammation were reduced in older adult mice exposed twice a week to ultraviolet radiation (from 29 weeks of age), compared to mock-irradiated mice, with some evidence for reduced hepatic mRNAs for tnf and tgfß1 (not fatp2 nor fasN). Power analyses suggested that up to 24 mice per treatment would be required in future experiments to detect a significant effect on some markers of adiposity such as body weight gain. Our studies suggest frequent exposure to low levels of sunlight may reduce the severity of hepatic steatosis induced in older adults living in environments of high caloric intake.

High-Dose Intramuscular Vitamin D Provides Long-Lasting Moderate Increases in Serum 25-Hydroxvitamin D Levels and Shorter-Term Changes in Plasma Calcium.

The best management of vitamin D deficiency, defined as a 25-hydroxyvitamin D [(25(OH)D] level <50 nM, is unclear. Intramuscular (IM) injection of a large bolus of vitamin D (≥100 000 IU) is used, but its safety is uncertain. In 10 adults given an IM injection of 600 000IU vitamin D3, we measured at baseline and at 1, 2, 3, and 4 weeks postinjection the serum levels of vitamin D3, 25(OH)D3, 25(OH)D2, total 25(OH)D, 3-epi-25(OH)D3, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] using a standardized LC with tandem MS (MS/MS) assay; serum levels of 25(OH)D using the Abbott ARCHITECT i2000 immunoassay; and markers of bone metabolism. Bone markers and 25(OH)D (immunoassay) were remeasured at 24 weeks. All participants had baseline total 25(OH)D levels >50 nM. Serum 25(OH)D levels increased at 3, 4, and 24 weeks postinjection, peaking at 4 weeks [mean ± SEM of 126 ± 7.9 nM (immunoassay) and 100 ± 5.5 nM (LC-MS/MS)] but generally remained <125 nM, the upper limit recommended by the U.S. Institute of Medicine. Serum 24,25(OH)2D3 levels increased at 3 and 4 weeks postinjection. Serum ionized calcium levels were higher than baseline at 1, 3, and 4 weeks postinjection but remained within the clinically normal range. Other biochemical parameters, including other vitamin D metabolites, plasma alkaline phosphatase, and parathyroid hormone levels, were unchanged. IM injection of a large bolus of vitamin D effectively increases serum 25(OH)D levels without evidence of metabolic abnormality.

Sub-erythemal ultraviolet radiation reduces metabolic dysfunction in already overweight mice.

Exposure to sunlight may limit cardiometabolic risk. In our previous studies, regular exposure to sub-erythemal (non-burning) ultraviolet radiation (UVR) reduced signs of adiposity and cardiometabolic dysfunction in mice fed a high-fat diet. Some of the observed effects were dependent on skin release of nitric oxide after UVR exposure. Here, we examine the effects of sub-erythemal UVR on signs of adiposity and metabolic dysfunction in already overweight mice, comparing the effects of two sunlamps with distinct emitted light spectra. Mice were fed a high-fat diet from 8 weeks of age, with UVR administered twice a week from 14 weeks of age until they were killed at 20 weeks of age. Mice were irradiated with the same dose of UVB radiation (1 kJ/m2) from either FS40 (65% UVB, 35% UVA) or CLEO (4% UVB, 96% UVA) sunlamps, but substantially more UVA from the latter. FS40 UVR (but not CLEO UVR) significantly reduced mouse weights and weight gain, compared to mice fed a high-fat diet (only). These effects were dependent on nitric oxide. Conversely, CLEO UVR (but not FS40 UVR) significantly reduced circulating LDL cholesterol. Both light sources reduced fasting insulin levels, and the extent of hepatic steatosis; the latter was reversed by topical application of cPTIO, suggesting an important role for skin release of nitric oxide in preventing hepatic lipid accumulation. These results suggest that there may be a number of benefits achieved by regular exposure to safe (non-burning) levels of sunlight or UV-containing phototherapy, with effects potentially dependent on the predominance of the wavelengths of UVR administered.

Ultraviolet radiation, vitamin D and the development of obesity, metabolic syndrome and type-2 diabetes.

Obesity is increasing in prevalence in many countries around the world. Its causes have been traditionally ascribed to a model where energy intake exceeds energy consumption. Reduced energy output in the form of exercise is associated with less sun exposure as many of these activities occur outdoors. This review explores the potential for ultraviolet radiation (UVR), derived from sun exposure, to affect the development of obesity and two of its metabolic co-morbidities, type-2 diabetes and metabolic syndrome. We here discuss the potential benefits (or otherwise) of exposure to UVR based on evidence from pre-clinical, human epidemiological and clinical studies and explore and compare the potential role of UVR-induced mediators, including vitamin D and nitric oxide. Overall, emerging findings suggest a protective role for UVR and sun exposure in reducing the development of obesity and cardiometabolic dysfunction, but more epidemiological and clinical research is required that focuses on measuring the direct associations and effects of exposure to UVR in humans.

Response to the Boucher et al. Comments on Fleury et al. Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction. Int. J. Environ. Res. Public Health 2016, 13, 999.

We thank Boucher et al. [1] for their interest in our recently published review [2]. [...].

Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction.

Obesity is a significant burden on global healthcare due to its high prevalence and associations with chronic health conditions. In our animal studies, ongoing exposure to low dose ultraviolet radiation (UVR, found in sunlight) reduced weight gain and the development of signs of cardiometabolic dysfunction in mice fed a high fat diet. These observations suggest that regular exposure to safe levels of sunlight could be an effective means of reducing the burden of obesity. However, there is limited knowledge around the nature of associations between sun exposure and the development of obesity and cardiometabolic dysfunction, and we do not know if sun exposure (independent of outdoor activity) affects the metabolic processes that determine obesity in humans. In addition, excessive sun exposure has strong associations with a number of negative health consequences such as skin cancer. This means it is very important to "get the balance right" to ensure that we receive benefits without increasing harm. In this review, we detail the evidence around the cardiometabolic protective effects of UVR and suggest mechanistic pathways through which UVR could be beneficial.