Circulating GDF-15 differentially predicts neuroendocrine-cardiometabolic reactivity to acute mental stress in adults with and without metabolic syndrome: The SABPA study

Introduction: Growth Differentiation Factor-15 (GDF-15) is a TGF-β superfamily metabolic cytokine that has emerged as a stress-responsive metabolic hormone linked to the cardiovascular and metabolic pathology underlying metabolic syndrome (MetS). Its receptor, GFRAL, is localized primarily to the area postrema and nucleus tractus solitarius, suggesting it plays a key role in conveying systemic cellular energetic status to the central nervous system. Based on the premise that increased basal energetic demands reduce the bioenergetic capacity to mount physiologic stress responses, we hypothesized that circulating GDF-15 would be elevated and associated with more blunted neuroendocrine (cortisol, dehydroepiandrosterone (DHEA)), cardiac (amino terminal pro-B-type natriuretic peptide (NT-proBNP)), and metabolic (glucose and insulin) responses to acute mental stress in adults with versus without MetS. Methods: Participants from the SABPA study with MetS (n=190; age 46±9 y) and healthy controls (HC; n=191; 43±10 y) provided fasting blood samples before and 10 min after they completed the Stroop Color–Word Conflict test. Baseline GDF-15 was quantified, and cortisol, DHEA, NT-proBNP, glucose, and insulin were measured pre-and post-Stroop. MetS was defined as the presence of three of the six following characteristics: waist circumference >102cm for men and >88cm for women; triglycerides ≥ 150mg/dL; HDL-cholesterol 3.0mg/L. Differences in baseline characteristics were examined with independent t-tests. Moderated regression models were used to test the interactive effect of baseline GDF-15 and MetS status (i.e., GDF-15×MetS) on the change (∆%) in neuroendocrine and cardiometabolic parameters induced by acute mental-stress, adjusted for age, sex, ethnicity, alcohol use, smoking, and physical activity. Results: As expected, MetS participants had greater waist circumference (+17.9 cm), triglycerides (+0.8 mmol/L), fasting glucose (+17.8 mmol/L), insulin (+7.9 mmol/L), and CRP (+2.8 mg/L), and lower HDL-cholesterol (-0.3 mmol/L) than HC (all p< 0.001). At baseline, GDF-15 was higher in MetS than HC (5.1±0.5 vs 4.9±0.5 pg/mL, p< 0.001). Across the full sample, GDF-15 was associated with a lower cortisol (β=-0.97, R 2 =0.56; p=0.01), DHEA (β=-0.89, R 2 =0.68; p< 0.001), and insulin response (β=-0.23, R 2 =0.76; p< 0.001), but a greater NT-proBNP (β=0.47, R 2 =0.18; p=0.006) response to acute mental stress. However, MetS status significantly moderated the relation of GDF-15 with stress-induced changes in cortisol (GDF-15×MetS: β=0.74, R 2 =0.35; p=0.001), DHEA (β=0.31, R 2 =0.48; p< 0.001), NT-proBNP (β=-0.69, R 2 =0.25; p=0.015), glucose (β=-0.58, R 2 =0.16; p=0.028), and insulin (β=1.36, R 2 =0.62; p< 0.001). The positive interaction terms suggest that the inverse association between GDF-15 and neuroendocrine-metabolic stress reactivity was attenuated in MetS versus HC. Similarly, the negative interaction term for NT-proBNP also indicated that the positive association between GDF-15 and the cardiac stress response was blunted among individuals with MetS compared to HC. Conclusions: Among adults free from MetS, GDF-15 indexes a coordinated pattern of reduced neuroendocrine and increased cardiac stress reactivity, whereas in individuals with MetS these relationships are diminished, potentially reflecting reduced adaptive stress-response capacity against a background of chronic metabolic load. Together, these findings suggest that GDF-15 may be a biomarker of divergent stress-response phenotypes that differ by metabolic risk status. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.