Plasma Growth Differentiation Factor-15 Concentrations Research Articles

Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

Associations of circulating GDF15 with combined cognitive frailty and depression in older adults of the MARK-AGE study.

Growth differentiation factor-15 (GDF15) might be involved in the development of cognitive frailty and depression. Therefore, we evaluated cross-sectional associations of plasma GDF15 with combined cognitive-frailty-and-depression in older (i.e. ≥ 55years) and younger adults of the MARK-AGE study. In the present work, samples and data of MARK-AGE ("European study to establish bioMARKers of human AGEing") participants (N = 2736) were analyzed. Cognitive frailty was determined by the global cognitive functioning score (GCF) and depression by the Self-Rating Depression Scale (SDS score). Adults were classified into three groups: (I) neither-cognitive-frailty-nor-depression, (II) either-cognitive-frailty-or-depression or (III) both-cognitive-frailty-and-depression. Cross-sectional associations were determined by unadjusted and by age, BMI, sex, comorbidities and hsCRP-adjusted linear and logistic regression analyses. Cognitive frailty, depression, age and GDF15 were significantly related within the whole study sample. High GDF15 levels were significantly associated with both-cognitive-frailty-and-depression (adjusted β = 0.177 [0.044-0.310], p = 0.009), and with low GCF scores and high SDS scores. High GDF15 concentrations and quartiles were significantly associated with higher odds to have both-cognitive-frailty-and-depression (adjusted odds ratio = 2.353 [1.267-4.372], p = 0.007; and adjusted odds ratio = 1.414 [1.025-1.951], p = 0.035, respectively) independent of age, BMI, sex, comorbidities and hsCRP. These associations remained significant when evaluating older adults. We conclude that plasma GDF15 concentrations are significantly associated with combinedcognitive-frailty-and-depression status and, with cognitive frailty and depressive symptoms separately in old as well as young community-dwelling adults.

Effects of acute exercise and exercise training on plasma GDF15 concentrations and associations with appetite and cardiometabolic health in individuals with overweight or obesity – A secondary analysis of a randomized controlled trial

Growth Differentiation Factor 15 (GDF15) is seemingly involved in appetite control. Acute exercise increases GDF15 concentrations in lean humans, but acute and long-term effects of exercise on GDF15 in individuals with overweight/obesity are unknown. We investigated the effects of acute exercise and exercise training on GDF15 concentrations in individuals with overweight/obesity and associations with appetite and cardiometabolic markers. 90 physically inactive adults (20–45 years) with overweight/obesity were randomized to 6-months habitual lifestyle (CON, n=16), or isocaloric exercise of moderate (MOD, n=37) or vigorous intensity (VIG, n=37), 5 days/week. Testing was performed at baseline, 3, and 6 months. Plasma GDF15 concentrations, other metabolic markers, and subjective appetite were assessed fasted and in response to acute exercise before an ad libitum meal. Cardiorespiratory fitness, body composition, insulin sensitivity, and intraabdominal adipose tissue were measured. At baseline, GDF15 increased 18% (95%CI: 4; 34) immediately after acute exercise and 32% (16; 50) 60 min post-exercise. Fasting GDF15 increased 21% (0; 46) in VIG after 3 months (p=0.045), but this attenuated at 6 months (13% (−11; 43), p=0.316) and was unchanged in MOD (11% (−6; 32), p=0.224, across 3 and 6 months). Post-exercise GDF15 did not change in MOD or VIG. GDF15 was not associated with appetite or energy intake. Higher GDF15 was associated with lower cardiorespiratory fitness, central obesity, dyslipidemia, and poorer glycemic control. In conclusion, GDF15 increased in response to acute exercise but was unaffected by exercise training. Higher GDF15 concentrations were associated with a less favorable cardiometabolic profile but not with markers of appetite. This suggests that GDF15 increases in response to acute exercise independent of training state. Whether this has an impact on free-living energy intake and body weight management needs investigation.

Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men.

Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 ± 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of "baseline GDF-15 × time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences.

Plasma growth differentiation factor-15 in patients with "lone" atrial fibrillation.

BackgroundGrowth differentiation factor‐15 (GDF‐15) is a member of the transforming growth factor β superfamily, correlated with various stimuli, including cardiovascular disease. The association between plasma GDF‐15 level and “lone” AF, that is, AF of unknown etiology (UeAF), is uncertain.MethodsAll patients aged 60 years or younger. AF patients were hospitalized for primary catheter ablation. Patients with sinus rhythm admitted for other diseases during the same period were included in the control group. ELISA was used to measure plasma GDF‐15 concentrations.Results60 UeAF patients, 60 paroxysmal AF (PAF) patients, and 70 control patients were enrolled. The mean age was 44.6 years. In the UeAF group, no patients had traditional clinical risk factors. The plasma GDF‐15 level in the UeAF group was (1028.5 ± 180.5) pg/ml, higher than in the control group, and moderately lower than in the PAF group. In all patients, positive correlations were found between plasma GDF‐15 level and age (R = 0.210, p < 0.05), and between plasma GDF‐15 level and left atrial diameter (LAD; R = 0.338, p < 0.05; in the UeAF group: R = 0.475, p < 0.05; in the PAF group: R = 0.504, p < 0.05).ConclusionsOur study first investigated the role of GDF‐15 in UeAF. The plasma GDF‐15 level in UeAF patients was higher than in sinus rhythm patients and lower than in PAF patients. Moreover, GDF‐15 was positively correlated with age and LAD. The role of GDF‐15 in UeAF needs further study.

Growth differentiation factor 15 (GDF15) is associated with non-alcoholic fatty liver disease (NAFLD) in youth with overweight or obesity

ObjectiveGrowth differentiation factor 15 (GDF15) has been associated with food intake and weight regulation in response to metabolic stress. In animal models, it has been noted that it may play a role in the progression of non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children.DesignIn the current study, we explored the association of circulating plasma concentrations of GDF15 with NAFLD in youth with overweight/obesity, and whether changes in plasma concentrations in GDF15 parallel the changes in intrahepatic fat content (HFF%) over time.MethodsPlasma GDF15 concentrations were measured by ELISA in 175 youth with overweight/obesity who underwent an oral glucose tolerance test (OGTT) and magnetic resonance imaging (MRI) to assess intrahepatic, visceral, and subcutaneous fat. Baseline fasting GDF15 concentrations were measured in twenty-two overweight/obese youth who progressed (n = 11) or regressed (n = 11) in HFF% by more than 30% of original over a 2-year period.ResultsYouth with NAFLD had significantly higher plasma concentrations of GDF15 than those without NAFLD, independent of age, sex, ethnicity, BMI z-score (BMIz), and visceral fat (P = 0.002). During the OGTT, there was a decline in plasma GDF15 concentrations from 0 to 60 min, but GDF15 concentrations returned to basal levels by the end of the study. There was a statistically significant association between change in HFF% and change in GDF15 (P = 0.008; r2 = 0.288) over ~2 years of follow-up.ConclusionsThese data suggest that plasma GDF15 concentrations change with change in intrahepatic fat content in youth with overweight/obesity and may serve as a biomarker for NAFLD in children.

Identification of traumatic acid as a potential plasma biomarker for sarcopenia using a metabolomics-based approach.

BackgroundThe pathogenesis of sarcopenia is complex and has not been well explored. Identifying biomarkers is a promising strategy for exploring the mechanism of sarcopenia. This study aimed to identify potential biomarkers of sarcopenia through a metabolomic analysis of plasma metabolites in elderly subjects (≥65 years of age) vs. younger adults (<65 years of age).MethodsOf the 168 candidates in the Comprehensive Geriatric Assessment and Frailty Study of Elderly Outpatients, 24 elderly subjects (≥65 years of age) with sarcopenia were age and sex matched with 24 elderly subjects without sarcopenia. In addition, 24 younger adults were recruited for comparison. Muscle strength, gait speed, and metabolic and inflammatory parameters, including plasma tumour necrosis factor‐α, C‐reactive protein, irisin, and growth differentiation factor 15 (GDF‐15) levels were assessed. Metabolomic analysis was carried out using the plasma metabolites.ResultsSeventy‐two participants were enrolled, including 10 (41.6%) men and 14 (58.3%) women in both groups of elderly subjects. The median ages of elderly subjects with and without sarcopenia were 82 (range: 67–88) and 81.5 (range: 67–87) years, respectively. Among the 242 plasma metabolic peaks analysed among these three groups, traumatic acid was considered as a sarcopenia‐related metabolite. The plasma traumatic acid signal intensity level was significantly higher in elderly subjects with sarcopenia than in elderly subjects without sarcopenia [591.5 (inter‐quartile range, IQR: 491.5–664.5) vs. 430.0 (IQR: 261.0–599.5), P = 0.0063]. The plasma concentrations of traumatic acid were 15.8 (IQR: 11.5–21.7), 21.1 (IQR: 16.0–25.8), and 24.3 (IQR: 18.0–29.5) ppb in younger adults [age range: 23–37 years, 12 (50%) men], elderly subjects without sarcopenia, and elderly subjects with sarcopenia, respectively, thereby depicting an increasing tendency (P for trend = 0.034). This pattern was similar to that of GDF‐15, a recognized sarcopenia‐related factor. Plasma traumatic acid concentrations were also positively correlated with the presence of hypertension (r = 0.25, P = 0.034), glucose AC (r = 0.34, P = 0.0035), creatinine (r = 0.40, P = 0.0006), and GDF‐15 levels (r = 0.25, P = 0.0376), but negatively correlated with the Modification of Diet in Renal Disease‐simplify‐glomerular filtration rate (r = −0.50, P < 0.0001). Similarly, plasma GDF‐15 concentrations were associated with these factors.ConclusionsTraumatic acid might represent a potential plasma biomarker of sarcopenia. However, further studies are needed to validate the results and investigate the underlying mechanisms.

Relationship between plasma growth differentiation factor-15 levels and diabetic retinopathy in individuals with type 2 diabetes

The purpose of our study was to investigate the relationship between plasma growth differentiation factor-15 (GDF-15) concentrations and diabetic retinopathy in patients with type 2 diabetes mellitus (DM). We evaluated 235 patients with type 2 DM in a cross-sectional study. Significantly increased levels of the plasma GDF-15 were found in individuals with diabetic retinopathy versus those without. According to the degree of diabetic retinopathy, there was a significant difference in the average plasma GDF-15 levels (no diabetic retinopathy, 1114 ng/L; nonproliferative diabetic retinopathy, 1327 ng/L; proliferative diabetic retinopathy, 1445 ng/L; p for trend = 0.035) after adjustments for confounders. Logistic regression analyses indicated that plasma GDF-15 concentrations were significantly associated with diabetic retinopathy (odds ratio per 1 standard deviation increment in the log-transformed value, 1.78; 95% confidence interval, 1.05–3.03, p = 0.032). Our study showed a significant positive relationship between plasma GDF-15 concentrations and diabetic retinopathy in type 2 DM patients.

A1630 Association between growth differentiation factor 15 and left ventricular hypertrophy in hypertensive patients and healthy adults

Objectives: Growth differentiation factor 15 (GDF-15) as an independent biomarker of cardiovascular diseases merits further evaluation. Methods: We studied the association between plasma GDF-15 levels and left ventricular hypertrophy (LVH) in hypertensive patients and healthy adults. Hypertensive LVH measurements were performed via echocardiography and analyzed using the cube formula, and human GDF-15 together with interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) concentrations were determined via enzyme-linked immunosorbent assay (ELISA). Results: A total of 302 participants were recruited for this clinical study. Circulating GDF-15, IL-6 and MMP-9 levels were significantly higher in LVH patients (n = 67) than in non-LVH patients (n = 172) and healthy controls (n = 63) (p < 0.001). After adjustment for confounders via multivariate logistic regression, elevated plasma GDF-15 concentrations remained independently associated with LVH in hypertensive patients. In addition, GDF-15 was positively correlated with IL-6 and MMP-9 levels in human plasma, respectively, suggesting that a link exists between GDF-15 expression and inflammation. We also calculated an optimal GDF-15 cut-off point with which LVH severity can be predicted in the current study. Conclusion: GDF-15 is associated with hypertensive LVH and may be a powerful biomarker with which LVH risk can be predicted in patients with hypertension.

Exercise increases circulating GDF15 in humans

ObjectiveThe growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance. Since exercise is a transient physiological stress that has pleiotropic effects on whole-body energy metabolism, we herein explored the effect of exercise on a) circulating GDF15 levels and b) GDF15 release from skeletal muscle in humans. MethodsSeven healthy males either rested or exercised at 67% of their VO2max for 1 h and blood was sampled from the femoral artery and femoral vein before, during, and after exercise. Plasma GDF15 concentrations were determined in these samples. ResultsPlasma GDF15 levels increased 34% with exercise (p < 0.001) and further increased to 64% above resting values at 120 min (p < 0.001) after the cessation of exercise. There was no difference between the arterial and venous GDF15 concentration before, during, and after exercise. During a resting control trial, GDF15 levels measured in the same subjects were unaltered. ConclusionsVigorous submaximal exercise increases circulating GDF15 levels in humans, but skeletal muscle tissue does not appear to be the source.

Usefulness of Growth Differentiation Factor-15 Levels to Predict Diabetic Cardiomyopathy in Asymptomatic Patients With Type 2 Diabetes Mellitus

Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that increased in patients with established type 2 diabetes mellitus (DM). Diabetic cardiomyopathy (DC), defined as left ventricular diastolic dysfunction (LVDD) in patients with type 2 DM in the absence of arterial hypertension, heart disease, or other heart disease, was assessed by GDF-15 levels in type 2 DM patients with and without DC. A total of 213 DM outpatients had blood samples drawn and on the same day (basal) underwent echocardiography and treadmill exercise testing. Plasma GDF-15 concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) at baseline. DC was diagnosed in the presence of LVDD, defined when early mitral valve flow velocity (E) and early diastolic lengthening velocity (E') ratio was E/E' ≥ 15. The prevalence of DC was 21.13%. GDF-15 levels were higher in patients with DC compared with those without DC (5,273 [8,708.4] vs 2,812.66 [7,662.1] pg/ml, respectively, p <0.001). We assessed predictors of DC using multivariate regression analysis. GDF-15 (odds ratio 9.9; 95% confidence interval [3.9 to 24.5], p <0.001) was the unique independent predictor of DC. The results of receiver operating characteristic curve show that the cut-off point of 3,812 pg/ml of GDF-15 was indicative for DC (AUC = 0.83, sensitivity = 82.2% and specificity = 70.2%, p <0.0001). In conclusion, GDF-15 represents a useful and novel tool to screen DC in patients with type 2 DM.