ORCID Profile
0000-0003-2550-9586
Current Organisation
The University of Edinburgh
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Publisher: Bioscientifica
Date: 04-2017
DOI: 10.1530/JOE-16-0616
Abstract: 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 sunl s 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/m 2 ) from either FS40 (65% UVB, 35% UVA) or CLEO (4% UVB, 96% UVA) sunl s, 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.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2021
DOI: 10.1101/2021.03.02.433510
Abstract: Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC) – which give rise to DCs – in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the ‘whitening’ effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.NIOX.2014.09.158
Abstract: Dietary nitrate supplementation has been shown to increase nitric oxide (NO) metabolites, reduce blood pressure (BP) and enhance exercise performance. Acute exposure to ultraviolet (UV)-A light also increases NO bioavailability and reduces BP. We conducted a randomized, counterbalanced placebo-controlled trial to determine the effects of UV-A light alone and in combination with nitrate on the responses to sub-maximal steady-state exercise and time trial (TT) performance. Nine cyclists (VO2max 53.1 ± 4.4 ml/kg/min) completed five performance trials comprising 10 min submaximal steady-state cycling followed by a 16.1 km TT. Following a familiarization the final four trials were preceded, in random order, by either (1) Nitrate gels (NIT) + UV-A, (2) Placebo (PLA) + UV-A, (3) NIT + Sham light (SHAM) and (4) PLA + SHAM (control). The NIT gels (2 × 60 ml gels, ~8.1 mmol nitrate) or a low-nitrate PLA were ingested 2.5 h prior to the trial. The light exposure consisted of 20 J/cm(2) whole body irradiation with either UV-A or SHAM light. Plasma nitrite was measured pre- and post-irradiation and VO2 was measured continuously during steady-state exercise. Plasma nitrite was higher for NIT + SHAM (geometric mean (95% CI), 332 (292-377) nM P = 0.029) and NIT + UV-A (456 (312-666) nM P = 0.014) compared to PLA + SHAM (215 (167-277) nM). Differences between PLA + SHAM and PLA + UV-A (282 (248-356) nM) were small and non-significant. During steady-state exercise VO2 was reduced following NIT + UVA (P = 0.034) and tended to be lower in NIT + SHAM (P = 0.086) but not PLA + UV-A (P = 0.381) compared to PLA + SHAM. Performance in the TT was significantly faster following NIT + UV-A (mean ± SD 1447 ± 41 s P = 0.005 d = 0.47), but not PLA + UV-A (1450 ± 40 s d = 0.41) or NIT + SHAM (1455 ± 47 s d = 0.28) compared to PLA + SHAM (1469 ± 52 s). These findings demonstrate that exposure to UV-A light alone does not alter the physiological responses to exercise or improve performance in a laboratory setting. A combination of UV-A and NIT, however, does improve cycling TT performance in this environment, which may be due to a larger increase in NO availability.
Publisher: Oxford University Press (OUP)
Date: 04-2001
DOI: 10.1046/J.1365-2672.2001.01291.X
Abstract: Nitric oxide is generated from sweat nitrite in the acidic environment of the skin surface and is thought to contribute to protection against infection. This study examined the sensitivity of Trichophyton mentagrophytes, T. rubrum, Candida albicans, Streptococcus pyogenes, Staphylococcus aureus and Propionibacterium acnes to acidified nitrite. Organisms were cultured in varying concentrations of nitrite and pH for different lengths of time, before being transferred to recovery medium. With the exception of Strep. pyogenes, addition of nitrite increased the antimicrobial activity of acid solutions against all organisms tested. The rank order of sensitivity was: C. albicans < T. rubrum < T. mentagrophytes < Staph. aureus < P. acnes, with P. acnes being most sensitive. This work has shown that acidified nitrite is microbiocidal to common cutaneous pathogens. The concentrations of nitrite required to kill pathogenic fungi and bacteria in in vitro assays were higher than the concentrations of nitrite measured in sweat. However, additional co-factors in vivo and in sweat may potentiate the effect of acidified nitrite. Pharmacological preparations of acidified nitrite are novel antimicrobial agents. These data suggest skin organisms which may be sensitive to this treatment.
Publisher: American Diabetes Association
Date: 13-10-2014
DOI: 10.2337/DB13-1675
Abstract: The role of vitamin D in curtailing the development of obesity and comorbidities such as the metabolic syndrome (MetS) and type 2 diabetes has received much attention recently. However, clinical trials have failed to conclusively demonstrate the benefits of vitamin D supplementation. In most studies, serum 25-hydroxyvitamin D [25(OH)D] decreases with increasing BMI above normal weight. These low 25(OH)D levels may also be a proxy for reduced exposure to sunlight-derived ultraviolet radiation (UVR). Here we investigate whether UVR and/or vitamin D supplementation modifies the development of obesity and type 2 diabetes in a murine model of obesity. Long-term suberythemal and erythemal UVR significantly suppressed weight gain, glucose intolerance, insulin resistance, nonalcoholic fatty liver disease measures and serum levels of fasting insulin, glucose, and cholesterol in C57BL/6 male mice fed a high-fat diet. However, many of the benefits of UVR were not reproduced by vitamin D supplementation. In further mechanistic studies, skin induction of the UVR-induced mediator nitric oxide (NO) reproduced many of the effects of UVR. These studies suggest that UVR (sunlight exposure) may be an effective means of suppressing the development of obesity and MetS, through mechanisms that are independent of vitamin D but dependent on other UVR-induced mediators such as NO.
Publisher: MDPI AG
Date: 05-05-2015
DOI: 10.3390/NU7053219
Publisher: Springer Science and Business Media LLC
Date: 07-03-2018
DOI: 10.1007/S00421-018-3835-X
Abstract: The present study investigated different doses of ultraviolet-A (UV-A) light on plasma nitric oxide metabolites and cardiorespiratory variables. Ten healthy male participants completed three experimental conditions, 7 days apart. Participants were exposed to no light (CON) 10 J cm 2 (15 min) of UV-A light (UVA10) and 20 J cm 2 (30 min) of UV-A light (UVA20) in a randomized order. Plasma nitrite [NO 2 − ] and nitrate [NO 3 − ] concentrations, blood pressure (BP), and heart rate (HR) were recorded before, immediately after exposure and 30 min post-exposure. Whole body oxygen utilization ( $${{\\dot{V}}}{\\rm O}_{2}$$ V ˙ O 2 ), resting metabolic rate (RMR) and skin temperature were recorded continuously. None of the measured parameters changed significantly during CON (all P 0.05). $${{\\dot{V}}}{\\rm O}_{2}$$ V ˙ O 2 and RMR were significantly reduced immediately after UVA10 ( P 0.05) despite no change in plasma [NO 2 − ] ( P 0.05). Immediately after exposure to UVA20, plasma [NO 2 − ] was higher ( P = 0.014) and $${{\\dot{V}}}{\\rm O}_{2}$$ V ˙ O 2 and RMR tended to be lower compared to baseline ( P = 0.06). There were no differences in [NO 2 − ] or $${{\\dot{V}}}{\\rm O}_{2}$$ V ˙ O 2 at the 30 min time point in any condition. UV-A exposure did not alter systolic BP, diastolic BP or MAP (all P 0.05). UV-A light did not alter plasma [NO 3 − ] at any time point (all P 0.05). This study demonstrates that a UV-A dose of 20 J cm 2 is necessary to increase plasma [NO 2 − ] although a smaller dose is capable of reducing $${{\\dot{V}}}{\\rm O}_{2}$$ V ˙ O 2 and RMR at rest. Exposure to UV-A did not significantly reduce BP in this cohort of healthy adults. These data suggest that exposure to sunlight has a meaningful acute impact on metabolic function.
Publisher: Frontiers Media SA
Date: 23-12-2020
Abstract: During the COVID-19 (coronavirus disease of 2019) pandemic, researchers have been seeking low-cost and accessible means of providing protection from its harms, particularly for at-risk in iduals such as those with cardiovascular disease, diabetes and obesity. One possible way is via safe sun exposure, and/or dietary supplementation with induced beneficial mediators (e.g., vitamin D). In this narrative review, we provide rationale and updated evidence on the potential benefits and harms of sun exposure and ultraviolet (UV) light that may impact COVID-19. We review recent studies that provide new evidence for any benefits (or otherwise) of UV light, sun exposure, and the induced mediators, vitamin D and nitric oxide, and their potential to modulate morbidity and mortality induced by infection with SARS-CoV-2 (severe acute respiratory disease coronavirus-2). We identified substantial interest in this research area, with many commentaries and reviews already published however, most of these have focused on vitamin D, with less consideration of UV light (or sun exposure) or other mediators such as nitric oxide. Data collected to-date suggest that ambient levels of both UVA and UVB may be beneficial for reducing severity or mortality due to COVID-19, with some inconsistent findings. Currently unresolved are the nature of the associations between blood 25-hydroxyvitamin D and COVID-19 measures, with more prospective data needed that better consider lifestyle factors, such as physical activity and personal sun exposure levels. Another short-coming has been a lack of measurement of sun exposure, and its potential to influence COVID-19 outcomes. We also discuss possible mechanisms by which sun exposure, UV light and induced mediators could affect COVID-19 morbidity and mortality, by focusing on likely effects on viral pathogenesis, immunity and inflammation, and potential cardiometabolic protective mechanisms. Finally, we explore potential issues including the impacts of exposure to high dose UV radiation on COVID-19 and vaccination, and effective and safe doses for vitamin D supplementation.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2019
DOI: 10.1007/S00125-019-05022-5
Abstract: 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. 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). 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. 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.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/IMCB.12460
Abstract: Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high-fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPCs)-which give rise to DCs-in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the 'whitening' effect of eating a high-fat diet upon interscapular (i) BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPCs and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional DCs (cDCs) increased in both of these tissues. When compared with a low-fat diet, consumption of a high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed the high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin [blocked using the scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO)], but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction .
Publisher: Oxford University Press (OUP)
Date: 10-08-2023
DOI: 10.1093/BJD/LJAD284
Abstract: Sleep disturbance is a prominent symptom of atopic dermatitis (AD) and can result in insomnia, daytime fatigue, drowsiness, reduced productivity, and impaired quality of life (QoL). The DUPISTAD (Dupilumab Effect on Sleep in AD Patients) phase 4 randomized double-blinded placebo-controlled study evaluated the impact of dupilumab treatment on sleep and other patient- and physician-reported outcomes. Adults with moderate-to-severe AD were randomized 2:1 to dupilumab 300 mg once every 2 weeks (q2w) or placebo for 12 weeks concomitant topical corticosteroids were permitted. Patients subsequently entered an open-label phase and received dupilumab 300 mg q2w for a further 12 weeks. The primary endpoint was percentage change from baseline to Week 12 in sleep quality, assessed using a novel numeric rating scale (NRS). Secondary and exploratory endpoints included percent change in peak pruritus NRS (PP NRS), change in SCORing Atopic Dermatitis (SCORAD), SCORAD sleep visual analog scale (VAS), Eczema Area and Severity Index, Patient Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score, and the Epworth Sleepiness Scale (ESS). Sleep diary and wrist actigraphy measurements were recorded throughout the study. In total, 127 patients received dupilumab and 61 placebo. Demographic and baseline disease characteristics were balanced between groups. Sleep quality NRS significantly improved in dupilumab-treated patients by Week 12 versus placebo (LSMD-15.5%, P& .001). PP NRS (LSMD -27.9%, P& .001), SCORAD (LSMD -15.1, P& .001), SCORAD sleep VAS (LSMD -2.1, P& .001), and PROMIS T-score (LSMD -3.6, P& .001) were also significantly improved at Week 12 with dupilumab versus placebo. The overall percentage of patients reporting treatment-emergent adverse events was lower in the dupilumab group (56.7%) than in the placebo group (67.2%). Dupilumab significantly improved sleep quality and perception of sleep continuity, itch, metrics of AD severity, and QoL in adults with moderate-to-severe AD, with an acceptable safety profile versus placebo. ClinicalTrials.gov: NCT04033367
Publisher: MDPI AG
Date: 13-07-2020
Abstract: This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer’s disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5–30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR.
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0190-9622(97)70307-4
Abstract: The development of research questions and the subsequent hypotheses are prerequisites to defining the main research purpose and specific objectives of a study. Consequently, these objectives determine the study design and research outcome. The development of research questions is a process based on knowledge of current trends, cutting-edge studies, and technological advances in the research field. Excellent research questions are focused and require a comprehensive literature search and in-depth understanding of the problem being investigated. Initially, research questions may be written as descriptive questions which could be developed into inferential questions. These questions must be specific and concise to provide a clear foundation for developing hypotheses. Hypotheses are more formal predictions about the research outcomes. These specify the possible results that may or may not be expected regarding the relationship between groups. Thus, research questions and hypotheses clarify the main purpose and specific objectives of the study, which in turn dictate the design of the study, its direction, and outcome. Studies developed from good research questions and hypotheses will have trustworthy outcomes with wide-ranging social and health implications.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Richard Weller.