Obesity in chronic inflammation using rheumatoid arthritis as a model: definition, significance, and effects of physical activity & lifestyle

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of PhilosophyBackground: Inflammation is the natural reaction of the body to an antigen. In some conditions, this reaction continues even after the elimination of the antigen, entering a chronic stage; it targets normal cells of the body and causes extensive damage. Rheumatoid arthritis (RA) is such a condition. It associates with significant metabolic alterations that lead to changes in body composition and especially body fat (BF) increases. In the general population, increased body fat (i.e. obesity) associates with a number of health disorders such as systemic low grade inflammation and a significantly increased risk for cardiovascular disease (CVD). Both effects of obesity could have detrimental effects in RA. Increased inflammation could worsen disease activity while obesity could further increase the already high CVD risk in RA. However, obesity in RA has attracted minimal scientific attention. Aims: The present project aimed to: 1) assess whether the existing measures of adiposity are able to identify the changes in body composition of RA patients, 2) if necessary develop RA-specific measures of adiposity, 3) investigate the association of obesity with disease characteristics and CVD profile of the patients, 4) and identify factors that might affect body weight and composition in these patients. Methods: A total of 1167 volunteers were assessed. Of them 43 suffered from osteoarthritis and 82 were healthy controls. These, together with 516 RA patients were used in the first study. Their body mass index (BMI), BF, and disease characteristics were assessed. In the second, third, fourth and fifth studies a separate set of 400 RA patients was assessed. In addition to the above assessments, their cardiovascular profile and more detailed disease characteristics were obtained. For the final study, 126 RA patients were assessed for all the above and also data on their physical activity levels and their diet were collected. Results: Assessments of adiposity for the general population are not valid for RA patients. Thus, we proposed RA-specific measures of adiposity. These are able to better identify RA patients with increased BF. We were also able to find associations between obesity and disease activity. Both underweight and obese RA patients had more active disease compared to normal-weight patients. Obese patients had significantly worse CVD profile compared to normal-weight. The newly devised measures of adiposity were able to identify those at increased risk. However, not all obese individuals were unhealthy and not all normal-weight healthy. Among our patients we were able to identify subtypes of obesity with distinct phenotypic characteristics that warrant special attention. Finally, we were able to identify factors that influence body weight and composition. Cigarette smoking protected against obesity while its cessation associated with increased adiposity. Physical activity was also found to be protective against obesity while diet or inflammation of the disease failed to produce any significant results. Conclusions: Obesity is a significant threat to the health of RA patients. The measures of adiposity developed herein should be used to identify obese RA patients. Physical activity seems like the sole mode for effective weight management in this population. Health and exercise professionals should actively encourage their patients to exercise as much as they can. This study has created more questions than it answered; further research in the association of obesity and inflammation, as well as in ways to treat it, is essential

Body-size phenotypes and cardiometabolic risk in Rheumatoid Arthritis

Objectives: Obesity is a significant contributor to metabolic complications. However, such complications are not uniform in people with similar body-size. The existence of normal-weight individuals with and obese individuals without metabolic complications has been described in the general population and is important in the context of cardiovascular disease (CVD). This has not been investigated in rheumatoid arthritis (RA), a condition associated with increased cardiometabolic risk. This study aims to identify the prevalence and predictors of body-size phenotypes in RA and investigate their associations with CVD risk. Methods: Body mass index (BMI: kg/m2), body fat (BF) and fat free mass (FFM), RA characteristics and CVD risk factors were assessed in 363 (262 females) volunteers with RA. Abnormal cardiometabolic status was defined as the presence of >1 of the following: hypertension, increased triglycerides or increased Low or reduced High Density Lipoprotein, high glucose, insulin resistance. Results: Among normal-weight, overweight, and obese participants 25%, 45.8%, 57.1% respectively were metabolically abnormal. Old age (B= 1.032, err=0.011; p= 0.005), waist circumference (B= 1.057, err= 0.011; p= 0.000), and smoking cessation (B= 1.425, err= 0.169; p=0.036) were significant predictors for metabolic abnormality. Conclusions: A significant number of RA patients present with different body-size and metabolic phenotypes. BMI alone is not a sufficient indicator of cardiometabolic risk in RA; this may have significant implications in their CVD risk evaluation. Body fat distribution seems to be a significant contributor to such abnormalities. Further research is needed, focusing on the metabolic properties of specific adipose depots of RA patient

Obesity in chronic inflammation using rheumatoid arthritis as a model : definition, significance, and effects of physical activity & lifestyle

Background: Inflammation is the natural reaction of the body to an antigen. In some conditions, this reaction continues even after the elimination of the antigen, entering a chronic stage; it targets normal cells of the body and causes extensive damage. Rheumatoid arthritis (RA) is such a condition. It associates with significant metabolic alterations that lead to changes in body composition and especially body fat (BF) increases. In the general population, increased body fat (i.e. obesity) associates with a number of health disorders such as systemic low grade inflammation and a significantly increased risk for cardiovascular disease (CVD). Both effects of obesity could have detrimental effects in RA. Increased inflammation could worsen disease activity while obesity could further increase the already high CVD risk in RA. However, obesity in RA has attracted minimal scientific attention. Aims: The present project aimed to: 1) assess whether the existing measures of adiposity are able to identify the changes in body composition of RA patients, 2) if necessary develop RA-specific measures of adiposity, 3) investigate the association of obesity with disease characteristics and CVD profile of the patients, 4) and identify factors that might affect body weight and composition in these patients. Methods: A total of 1167 volunteers were assessed. Of them 43 suffered from osteoarthritis and 82 were healthy controls. These, together with 516 RA patients were used in the first study. Their body mass index (BMI), BF, and disease characteristics were assessed. In the second, third, fourth and fifth studies a separate set of 400 RA patients was assessed. In addition to the above assessments, their cardiovascular profile and more detailed disease characteristics were obtained. For the final study, 126 RA patients were assessed for all the above and also data on their physical activity levels and their diet were collected. Results: Assessments of adiposity for the general population are not valid for RA patients. Thus, we proposed RA-specific measures of adiposity. These are able to better identify RA patients with increased BF. We were also able to find associations between obesity and disease activity. Both underweight and obese RA patients had more active disease compared to normal-weight patients. Obese patients had significantly worse CVD profile compared to normal-weight. The newly devised measures of adiposity were able to identify those at increased risk. However, not all obese individuals were unhealthy and not all normal-weight healthy. Among our patients we were able to identify subtypes of obesity with distinct phenotypic characteristics that warrant special attention. Finally, we were able to identify factors that influence body weight and composition. Cigarette smoking protected against obesity while its cessation associated with increased adiposity. Physical activity was also found to be protective against obesity while diet or inflammation of the disease failed to produce any significant results. Conclusions: Obesity is a significant threat to the health of RA patients. The measures of adiposity developed herein should be used to identify obese RA patients. Physical activity seems like the sole mode for effective weight management in this population. Health and exercise professionals should actively encourage their patients to exercise as much as they can. This study has created more questions than it answered; further research in the association of obesity and inflammation, as well as in ways to treat it, is essential.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Vascular Structure and Functional Responses to Consecutive High-Fat Feeding between Insulin Treatment Regimens in Adults with Type 1 Diabetes and Matched Controls.

Background Impaired vascular health is prevalent in type 1 diabetes (T1D); however, it remains unknown whether di!erent insulin treatment regimens mediate indices of vascular structure or function. Methods Sixteen individuals with T1D receiving either multiple daily injection therapy (MDI; n=8; age: 32±13years; BMI:26.0±5.9kg.m2; HbA1c:53.7±11.2mmol/mol [7.1±3.2%]) or continuous subcutaneous insulin infusion (CSII; n=8; age:35±18years; BMI:26.3±4.6kg.m2; HbA1c: 58.6±9.7mmol/mol [7.5±3.0%]) and ten matched controls (CON; age:31±13years; BMI: 24.3±2.9kg.m2) consumed two high fat (HF) meals at 4-hour intervals. Carotid artery intima-media thickness (CIMT) and flow mediated dilation (FMD) was assessed at baseline, with further FMD assessment at 3-hrs following the ingestion of each meal using high resolution B-mode ultrasound. Bolus insulin dose was standardised using the carbohydrate-counting method. Results CIMT was significantly higher in individuals with T1D compared to controls (p=0.039); treatment stratification within T1D revealed MDI mediated this e!ect (MDI vs. CON: p=0.049; CSII vs. CON: p=0.112). FMD remained unchanged following the first meal (p=0.204) but was significantly impaired following the second meal (p=<0.001); post- hoc analysis revealed MDI mediated this e!ect of impaired FMD after the second meal (MDI vs. CON: p=0.048; CSII vs. CON: p=0.416). Conclusions Our findings indicate that patients treated with MDI therapy have higher CIMT (a structural marker of subclinical atherosclerosis) compared to controls but not CSII therapy. FMD was impaired following a second HF meal irrespective of a diabetes status. Considering the pre-existing heightened cardiovascular disease risk in T1D therapeutic strategies to reduce postprandial risk warrants further research

ACSM pre-participation health screening guidelines: a UK university cohort perspective.

PURPOSE: Pre-participation health screening is recommended to detect individuals susceptible to serious adverse cardiovascular complications during exercise. Although expert opinion and best available scientific evidence have informed recent modifications, there remains limited experimental data to support or refute current practice. We therefore aimed to quantify the impact of change to the ACSM pre-participation health screening guidelines on risk classification and referral for medical clearance in a large cohort of undergraduate university students. METHODS: Participants attended the laboratory on a single occasion to undergo pre-participation health screening. Information concerning health status was obtained via self-report questionnaire and objective physiological assessment with all data recorded electronically and evaluated against ACSM screening guidelines (9 and 10 Edition). RESULTS: Five-hundred and fifty-three students completed the study. The 9th Edition screening guidance resulted in eighty-two (15%) subjects classified as high-risk, almost one quarter (24%) classified as moderate-risk, and almost two-thirds (61%) classified as low-risk. In comparison, the updated 10 Edition screening guidance resulted in a significant reduction in those previously classified as either high-risk (5%) or moderate risk (2%), respectively. The majority of subjects (93%) were therefore cleared to begin a structured exercise programme. Taken together, approximately one-third (32%) fewer medical referrals were required when applying the updated 10 Edition guidance (χ (4) = 247.7, P<0.001). CONCLUSION: The updated ACSM 10 Edition pre-participation screening guidance reduces medical referrals by approximately one-third. These findings are in keeping with previous reports and thus serve to consolidate and justify recent modification - particularly when applied to young adult or adolescent populations. The findings and arguments presented should be used to refine and inform future guidance

Rheumatoid Cachexia: causes, significance and possible interventions

Rheumatoid arthritis is a chronic autoimmune disease characterised by joint pain and stiffness but also systemic mutli-organ involvement. Several features are due to excessive production of inflammatory cytokines, particularly tumour necrosis factor alpha, interleukin-1 and interleukin-6. These are implicated in both local synovial inflammation, which causes joint destruction, but also systemic inflammation, which can cause loss of body cell mass, amongst other phenomena. Body cell mass breakdown in rheumatoid arthritis leads to the classical, but largely ignored, metabolic abnormality known as rheumatoid cachexia. Cachexia is a very strong predictor of adverse functional outcome and death in many disease states. In this review we highlight the mechanisms linked with rheumatoid cachexia and discuss possible interventions that may limit this in patients with rheumatoid arthritis

The Effect of High-Fat Diet on Intramyocellular Lipid Content in Healthy Adults: A Systematic Review, Meta-Analysis, and Meta-Regression

\ua9 2024 The AuthorsFatty acids are stored within the muscle as intramyocellular lipids (IMCL). Some, but not all, studies indicate that following a high-fat diet (HFD), IMCL may accumulate and affect insulin sensitivity. This systematic review and meta-analysis aimed to quantify the effects of an HFD on IMCL. It also explored the potential modifying effects of HFD fat content and duration, IMCL measurement technique, physical activity status, and the associations of IMCL with insulin sensitivity. Five databases were systematically searched for studies that examined the effect of ≥3 d of HFD (&gt;35% daily energy intake from fat) on IMCL content in healthy individuals. Meta-regressions were used to investigate associations of the HFD total fat content, duration, physical activity status, IMCL measurement technique, and insulin sensitivity with IMCL responses. Changes in IMCL content and insulin sensitivity (assessed by hyperinsulinemic-euglycemic clamp) are presented as standardized mean difference (SMD) using a random effects model with 95% confidence intervals (95% CIs). Nineteen studies were included in the systematic review and 16 in the meta-analysis. IMCL content increased following HFD (SMD = 0.63; 95% CI: 0.31, 0.94, P = 0.001). IMCL accumulation was not influenced by total fat content (P = 0.832) or duration (P = 0.844) of HFD, physical activity status (P = 0.192), or by the IMCL measurement technique (P &gt; 0.05). Insulin sensitivity decreased following HFD (SMD = –0.34; 95% CI: –0.52, –0.16; P = 0.003), but this was not related to the increase in IMCL content following HFD (P = 0.233). Consumption of an HFD (&gt;35% daily energy intake from fat) for ≥3 d significantly increases IMCL content in healthy individuals regardless of HFD total fat content and duration of physical activity status. All IMCL measurement techniques detected the increased IMCL content following HFD. The dissociation between changes in IMCL and insulin sensitivity suggests that other factors may drive HFD-induced impairments in insulin sensitivity in healthy individuals. This trial was registered at PROSPERO as CRD42021257984

Evaluating the validity of a smartphone step-counter in adults with asthma: a proof-of-concept study

Introduction: Regular physical activity and structured exercise are often reported to be associated with improved asthma control - however the majority of published evidence is limited by short-term studies employing subjective measures of assessment (i.e. self-report / questionnaires). Modern smartphones typically include built-in activity sensors (i.e. possess the capability to monitor daily step-count) and thus may offer a cost-effective and pragmatic solution to the assessment of physical activity in clinical practice and/or research trials. The primary aim of this proof-of-concept study was therefore to evaluate the validity of the iPhone® (Apple Inc, USA) step-counter in adults with asthma and healthy controls. Methods: The study was conducted as a cross-sectional laboratory based-trial. Ten healthy adults with no prior history of respiratory disease and ten adults with a prior physician diagnosis of asthma were enrolled. All completed baseline clinical assessment followed by a standardised walking treadmill challenge consisting of 3 x 3-minute stages at pre-determined speeds: 2.5kph, 5.0kph and 7.5kph. Steps were recorded using the following devices: (i) Yamax Digiwalker™ SW-200 Pedometer (Yamax, UK), (ii) iPhone® step-counter (upper body arm-band), (iii) iPhone® step-counter (lower body trouser pocket) - and evaluated against a video-verified manual step-count (i.e. gold-standard comparator) conducted by the investigator (CR). Results: No difference was observed in manual total step-count between individuals with asthma (1018 steps) and healthy controls (1038 steps) (P=0.44). The iPhone® step-counter (both upper and lower body) provided close agreement with video-verified manual step-count, and importantly, outperformed the Yamax Digiwalker® SW-200 Pedometer across the majority of test stages. Specifically, the iPhone® (lower body) correlated strongly (r = 0.96; P<0.006) and produced the highest level of agreement with video-verified total step-count (mean bias: -11; limits of agreement: -43 to 21) (Table 1). Conclusion: Our findings indicate that the iPhone® provides an accurate estimate of step-count in adults with asthma and healthy controls completing a standardised laboratory-based treadmill test. Prior to implementation, further research is required to determine the validity and reliability of this approach during daily active / free living conditions

The role of microRNAs in regulating inflammation and exercise-induced adaptations in rheumatoid arthritis.

MicroRNAs (miRNAs) are endogenously generated single-stranded RNAs that play crucial roles in numerous biological processes, such as cell development, proliferation, differentiation, metabolism and apoptosis. They negatively regulate target gene expression by repressing translation of messenger RNA into a functional protein. Several miRNAs have been implicated in the development and progression of RA. They are involved in inflammatory and immune processes and are associated with susceptibility to RA and disease activity. They are also considered to be potential markers of disease activity or even therapeutic targets. Likewise, several miRNAs are affected acutely by exercise and regulate exercise-related adaptations in the skeletal muscle and cardiovascular system and aerobic fitness. Interestingly, some miRNAs affected by exercise are also important in the context of RA. Investigating these might increase our understanding of the effects of exercise in RA and improve exercise prescription and, potentially, disease management. In this review, we focus on the miRNAs that are associated with both RA and exercise and discuss their roles in (and potential interactions between) RA and exercise-induced adaptations