Robin Lengton

Aims/hypothesis: Adipocyte glucocorticoid (GC)-responsive transcripts are linked to lipid storage and insulin sensitivity, and South Asians develop insulin resistance at lower BMI than White Europeans. We tested whether modest short-term weight gain was associated with adipocyte GC-related transcripts differently by ancestry and whether within-person transcript changes were associated with dynamic insulin responses. Methods: In this exploratory secondary analysis of the GlasVEGAS study, White European ( n = 21) and South Asian ( n = 14) men underwent ~ 6% diet-induced weight gain. Isolated abdominal subcutaneous adipocytes were sampled at baseline and post-weight gain for RT-qPCR assessment of GC-responsive transcripts and related targets. Metabolic responses were characterised using a standardised mixed-meal test with 5 h profiles of glucose, insulin, C-peptide and triglycerides; hepatic triacylglycerol content was quantified by MRI. Results: Weight gain reduced FKBP5 (− 23.65 ± 8.82% in White Europeans; − 17.68 ± 11.62% in South Asians; p = 0.007) and TSC22D3 (also known as GILZ ; − 11.40 ± 2.83%; − 5.95 ± 4.01%; p = 0.001 for change with weight gain), with no ethnicity × intervention interaction ( p ≥ 0.26). HSD11B1 / HSD11B2 and IL2 / IL6 did not change. At baseline, FKBP5 and GILZ were associated with adiposity, liver fat and adipocyte size. Within-person Δ FKBP5 (post-weight gain minus baseline) correlated with Δpostprandial insulin ( r = 0.46, p = 0.006) and ΔC-peptide ( r = 0.34, p = 0.049). Δ GILZ correlated with Δfasting glucose ( r = − 0.40, p = 0.017) and Δpostprandial insulin ( r = 0.34, p = 0.049). In exploratory within-person analyses, changes in FKBP5 and GILZ were associated with changes in postprandial insulin-related measures. Conclusion/interpretation: Early modest weight gain downregulates adipocyte GC-responsive transcripts, with no statistically significant ethnicity-by-weight gain interaction detected in this modest-sized exploratory cohort, and dynamic transcript changes track insulin exposure. These findings implicate a potential link between dynamic insulin responses and adipocyte glucocorticoid-responsive transcription during early weight gain, linking adipocyte transcriptional responses to clinically relevant postprandial insulin physiology.

Objective: Chronic stress is linked to cardiometabolic diseases through increased glucocorticoid exposure, but the impact of daily life stress on glucocorticoid regulation and cardiometabolic health remains underexplored. This study investigated these associations. Design: This is a cross-sectional analysis of participants from the Netherlands Study of Depression and Anxiety (NESDA) without psychiatric diagnosis in the prior 6 months. Methods: We included 870 participants (64.7% female, median age 47.0 years). Daily life stress was assessed using the Daily Hassles Questionnaire (DHQ). Salivary cortisol was analyzed for 1-h awakening cortisol (4 time points), evening cortisol, and slope. Also an overnight 0.5 mg dexamethasone suppression test was performed. Associations between DHQ, glucocorticoid measures, and cardiometabolic health were studied using logistic and linear regressions. Results: After multivariable adjustment, each standard deviation (SD) increase in DHQ score was associated with 1.38 times (95% confidence interval [CI] 1.07; 1.77) higher odds of cardiovascular disease (CVD), but not diabetes, metabolic syndrome, or obesity. Higher DHQ scores were also associated with higher evening cortisol levels. In addition, each SD increase in cortisol suppression ratio was associated with 1.36 times (95% CI 1.08; 1.72) higher odds of CVD, but not diabetes, metabolic syndrome, or obesity. No interactions between DHQ and glucocorticoid measures on CVD were observed. Conclusion: A higher cortisol suppression ratio, indicative of increased glucocorticoid sensitivity, and increased daily hassles were both independently associated with having CVD. The absence of interaction suggests they influence CVD through separate pathways, highlighting the need for further research to better understand stress mechanisms and identify “stress profiles” most closely linked to cardiometabolic diseases.

Summary: Chronic stress, characterized by increased long‐term exposure to the glucocorticoid hormone cortisol, is increasingly linked to obesity development. Still, various knowledge gaps persist, including on underlying pathophysiological mechanisms. The aim of the current review is to provide the latest insights on the connection between stress and obesity. We discuss three biological stress systems—the autonomic nervous system, the hypothalamus–pituitary–adrenal (HPA) axis and the immune system—and their link with obesity, with a particular focus on the HPA axis. The role of cortisol and its regulatory variations (including glucocorticoid rhythmicity and altered sensitivity) in adipose tissue biology and obesity development is discussed. Moreover, we highlight the physiological, affective, cognitive and behavioural dimensions of the stress response offering a deeper understanding of how stress contributes to obesity development and vice versa. Finally, stress as a treatment target for obesity is discussed. We conclude that the link between stress and obesity is complex and multifaceted, influenced by physiological, affective, cognitive and behavioural stress response mechanisms, which especially when chronically present, play a key role in the development of obesity and associated cardiometabolic diseases. This necessitates integrated approaches tailored to individual needs, including lifestyle modifications, behavioural interventions, psychosocial support and possible additional pharmacological interventions.

Purpose: Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and adiponectin mediated these associations. Methods: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, 6671 participants (45–65 y) were included. We defined CKD as eGFR 2 and/or moderately increased albuminuria. The percentage of mediation was calculated using general structural equation modeling, adjusted for potential confounding factors age, sex, smoking, ethnicity, physical activity and Dutch healthy diet index. Results: At baseline mean (SD) age was 56 (6), BMI 26.3 (4.4), 44% men, and 4% had CKD. Higher BMI and TBF were associated with 1.08 (95%CI 1.05; 1.11) and 1.05-fold (95%CI 1.02; 1.08) increased odds of CKD, respectively. As adiponectin was not associated with any of the outcomes, it was not studied further as a mediating factor. The association between BMI and CKD was 8.5% (95%CI 0.5; 16.5) mediated by diabetes and 22.3% (95%CI 7.5; 37.2) by hypertension. In addition, the association between TBF and CKD was 9.6% (95%CI −0.4; 19.6) mediated by diabetes and 22.4% (95%CI 4.2; 40.6) by hypertension. We could not confirm mediation by leptin in the association between BMI and CKD (35.6% [95%CI −18.8; 90.3]), nor between TBF and CKD (59.7% [95%CI −7.1; 126.6]). Conclusion: Our results suggest that the relations between BMI, TBF and CKD are in part mediated by diabetes and hypertension.

Background: Obesity is a multifactorial, chronic, progressive disease associated with decreased health-related quality of life, comorbidities, and increased mortality risk. Lifestyle interventions, focusing on dietetics, physical exercise, and behavioral therapy, are a cornerstone of therapy. Despite this very multidisciplinary treatment approach, the definition of treatment success is often based only on a weight loss of ≥ 5%. However, the heterogeneous nature of obesity may necessitate a more comprehensive approach to assessing treatment effects. Objectives: Here, we describe changes in physiological, psychological, and behavioral health after a multidisciplinary combined lifestyle intervention (CLI). Additionally, we investigated whether these changes were related to weight loss. Methods: This prospective observational longitudinal study comprised 96 adults with obesity (73 women, 81 Caucasian) participating in a CLI at the Obesity Center CGG, Erasmus University Medical Center, Rotterdam, the Netherlands. The 1.5-year intervention comprised multidisciplinary professional guidance towards a healthy diet, increased physical activity, and included cognitive behavioral therapy. Physiological health outcomes, psychological well-being, eating behavior, and physical activity were assessed after ten weeks and 1.5 years and compared to baseline. Results: An average of 5.2% weight loss (-6.0 kg) was accompanied by a mean 9.8% decrease in fat mass (-5.9 kg; both P < 0.001) and significant improvements in metabolism, hormonal status, and immune parameters (all P < 0.05). Moreover, we observed decreased psychopathology, increased quality of life, and decreased disordered eating (all P < 0.05). Weight loss correlated with most metabolic changes (all P < 0.05) but not with most psychological/behavioral changes. Conclusions: Combined lifestyle intervention in patients with obesity was accompanied by significant improvements in body weight and body composition along with cardiometabolic, endocrine, immunological, psychological, and behavioral improvements. Interestingly, most changes in psychological and behavioral health occurred independently of weight loss. Obesity treatment success should be evaluated based on a combination of physical and patient-reported outcomes rather than weight loss alone.

Chronic kidney disease–associated pruritus (CKD-aP) is common in dialysis patients, and is associated with lower quality of life and increased risk of death. We investigated the association between residual estimated glomerular filtration rate (eGFR), dialysis adequacy or serum phosphate level and CKD-aP in incident dialysis patients. A total of 1256 incident hemodialysis (HD) and 670 peritoneal dialysis (PD) patients (>18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) study were included (1997–2007) and followed until death, transplantation or a maximum of 10 years. CKD-aP was measured using a single item of the Kidney Disease Quality of Life Instrument-36. The associations were studied by logistic and linear regression analyses, adjusted for potential baseline confounders. At baseline mean (standard deviation) age was 60 (16) years, 62% were men and median (interquartile range) residual eGFR was 3.4 (1.7; 5.3) mL/min/1.73 m². The prevalence of CKD-aP (∼70%) was similar in HD and PD. It was observed that 12 months after starting dialysis (after multivariable adjustment) each 1 mL/min/1.73 m² higher residual eGFR, one unit higher total weekly Kt/V, or 1 mmol/L lower serum phosphate level was associated with lower burden of CKD-aP in HD and PD patients of –0.05 (95% CI –0.09; –0.02) and –0.09 (95% CI –0.13; –0.05), –0.15 (95% CI –0.26; –0.05) and –0.35 (95% CI –0.54; –0.16), and of –0.34 (95%CI: –0.51; –0.17) and –0.45 (95%CI: –0.71; –0.19), respectively. We found no association between dialysis Kt/V and CKD-aP. Higher residual eGFR and lower serum phosphate level, but not the dialysis dose, were related with lower burden of CKD-aP in dialysis patients.

Background: Depression is associated with lower quality of life and increased risk of mortality. The prevalence of depression in chronic dialysis patients, as well as in patients with diabetes, is more than 20%. It is debated whether use of beta-blockers increases the risk of depression. Therefore, we examined in chronic dialysis patients with and without diabetes, the association between beta-blockers and depressive symptoms. Methods: Data were collected from the DIVERS-I study, a multicentre prospective cohort among chronic dialysis patients in the Netherlands. Depressive symptoms were assessed with the Beck Depression Inventory (BDI-II). We defined depressive symptoms as a BDI-II score ⩾16. The cross-sectional association at baseline between depressive symptoms and beta-blocker use in chronic dialysis patients, was studied by multivariable logistic regression adjusted for potential confounders. Results: We included 684 chronic dialysis patients, of whom 43% had diabetes mellitus, and 57% used a beta-blocker of which 97% were lipophilic. After multivariable adjustment, the OR (95% CI) for depressive symptoms in patients with compared to without diabetes was 1.41 (1.00-1.98), and in beta-blocker users compared to non-users 1.12 (0.80-1.56), respectively. Dialysis patients with diabetes and beta-blocker use compared to those without diabetes and not using beta-blockers had an OR of 1.73 (1.12-2.69) for depressive symptoms. The association was stronger in dialysis patients with diabetes and lipophilic beta-blocker use with an OR of 1.77 (1.14-2.74). Conclusions: We found a possible association between lipophilic beta-blocker use and depressive symptoms in chronic dialysis patients with diabetes.

Background: Itching (pruritus) is common in dialysis patients, but little is known about its impact on health-related quality of life (HRQOL), sleep problems and psychological symptoms. This study investigates the impact of itching in dialysis patients by looking into the persistence of itching, the effect of itching on the course of HRQOL and the combined effect of itching with sleep problems and with psychological symptoms on HRQOL. Methods: Data were obtained from the RENINE/PROMs registry and included 2978 dialysis patients who completed patient-reported outcome measures between 2018 and 2020. Itching, sleep problems and psychological symptoms were assessed with the Dialysis Symptom Index (DSI) and HRQOL with the 12-item Short Form Health Survey. Effects of itching on HRQOL and interactions with sleep problems and psychological symptoms were investigated cross-sectionally and longitudinally using linear regression and linear mixed models. Results: Half of the patients experienced itching and in 70% of them, itching was persistent. Itching was associated with a lower physical and mental HRQOL {−3.35 [95% confidence interval (CI) −4.12 to −2.59) and −3.79 [95% CI −4.56 to −3.03]}. HRQOL remained stable during 2 years and trajectories did not differ between patients with or without itching. Sleep problems (70% versus 52%) and psychological symptoms (36% versus 19%) were more common in patients with itching. These symptoms had an additional negative effect on HRQOL but did not interact with itching. Conclusions: The persistence of itching, its impact on HRQOL over time and the additional effect on HRQOL of sleep problems and psychological symptoms emphasize the need for recognition and effective treatment of itching to reduce symptom burden and improve HRQOL.

Summary: Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long‐term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups.The effect of GCs is not only determined by the plasma concentration of GCs but also by individual differences in GC sensitivity and the target tissue, which can be analyzed by functional GC assays. GC sensitivity is influenced by multiple genetic and acquired (e.g., disease‐related) factors, including intracellular GC availability, hormone binding affinity, and expression levels of the GC receptors and their isoforms, as well as factors involved in the modulation of gene transcription. Interindividual differences in GC sensitivity also play a role in the response to exogenous GCs, with respect to both therapeutic and adverse effects.Accordingly, in this review, we summarize current knowledge on mechanisms that influence GC sensitivity and their relationships with obesity and discuss personalized treatment options targeting the GC receptor.