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Introduction: Stress predicts unhealthy eating, obesity, and metabolic deterioration, likely mediated by altered levels of appetite- and metabolism-regulating hormones. Yet, evidence regarding the association between long-term stress and levels of appetite-regulating hormones in humans is lacking. Methods: We included 65 patients with obesity (44 women) to investigate the cross-sectional association of biological stress (scalp hair cortisol and cortisone) and psychological stress (Perceived Stress Scale) with overnight-fasted serum levels of the hormonal appetite regulators leptin, adiponectin, insulin, pancreatic polypeptide, gastric-inhibitory peptide, peptide tyrosine-tyrosine, cholecystokinin and agouti-related protein, adjusted for age, sex and body-mass-index. Results: Hair cortisone and, in trend, hair cortisol were positively associated with cholecystokinin (p=0.003 and p=0.058, respectively). No other associations between stress measures and hormonal appetite regulators were observed. Conclusion: Long-term biological stress, measured using scalp hair glucocorticoid levels, is associated with elevated levels of circulating cholecystokinin, indicating a link between long-term stress and hormonal appetite signaling.

Abstract Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP‐1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26 weeks of treatment with daily liraglutide (n = 44) or placebo (n = 50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26 weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. Highlights What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP‐1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26 weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite‐suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

Objectives: Cold exposure is linked to cardiometabolic benefits. Cold activates brown adipose tissue (BAT), increases energy expenditure, and induces secretion of the hormones fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). The cold-induced increase in energy expenditure exhibits a diurnal rhythm in men. Therefore, we aimed to investigate the effect of cold exposure on serum FGF21 and GDF15 levels in humans and whether cold-induced changes in FGF21 and GDF15 levels differ between morning and evening in males and females. Method: In this randomized cross-over study, serum FGF21 and GDF15 levels were measured in healthy lean males (n = 12) and females (n = 12) before, during, and after 90 min of stable cold exposure in the morning (07:45 h) and evening (19:45 h) with a 1-day washout period in between. Results: Cold exposure increased FGF21 levels in the evening compared to the morning both in males (+61% vs −13%; P < 0.001) and in females (+58% vs +8%; P < 0.001). In contrast, cold exposure did not significantly modify serum GDF15 levels, and no diurnal variation was found. Changes in FGF21 and GDF15 levels did not correlate with changes in cold-induced energy expenditure in the morning and evening. Conclusion: Cold exposure increased serum FGF21 levels in the evening, but not in the morning, in both males and females. GDF15 levels were not affected by cold exposure. Thus, this study suggests that the timing of cold exposure may influence cold-induced changes in FGF21 levels but not GDF15 levels and seems to be independent of changes in energy expenditure.