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. Author manuscript; available in PMC: 2023 Feb 28.
Published in final edited form as: Obes Surg. 2022 Jun 8;32(8):2641–2648. doi: 10.1007/s11695-022-06140-7

GDF15 and Cortisol Response to Meal Tolerance Test in Post-Sleeve Gastrectomy Patients with Weight Regain

Jenny Pena Dias 1,2, Olga Carlson 2, Michael Schweitzer 3, Michelle Shardell 4, Jeanne M Clark 1,5, Todd T Brown 1,5, Josephine M Egan 2, Clare J Lee 1
PMCID: PMC9972254  NIHMSID: NIHMS1872447  PMID: 35672598

Abstract

Background

Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG.

Methods

Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight − nadir)/(preoperative weight − nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0–240 min) after 3–6 years post-bariatric surgery.

Results

All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m2. Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m2, non-WR: 30.3 ± 3.5 kg/m2, p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 μg*min/dL, p = 0.015)). Incretin response did not differ between the groups.

Conclusions

GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

Keywords: Weight regain, GDF15, Cortisol, Bariatric surgery

Graphical Abstract:

graphic file with name nihms-1872447-f0001.jpg

Introduction

Bariatric surgery is a highly effective treatment to reduce weight and comorbidities [1]. However, weight regain, often defined as regaining at least 10% of weight lost, occurs in many individuals after bariatric surgery [2], and factors contributing to weight regain remain poorly understood [3, 4]. Hormones such as growth/differentiation factor 15 (GDF15) and cortisol are two stress-stimulated hormones known to contribute to weight change in animal and in human studies [5, 6]. GDF15 is a biomarker of cellular stress predominantly expressed liver, lung, and kidney [5, 7, 8] but it may be expressed by almost any cell or tissue in response to various stressors [5, 9]. Pharmacological dose of GDF15 has been suggested as a satiety hormone with a potential to treat obesity as shown in several preclinical studies following its administration [10–12]. Indeed, greater degrees of weight loss after bariatric surgery [13, 14] have been associated with increased concentrations of circulating GDF15.

While studies after sleeve gastrectomy (SG) have reported an increase in anorexigenic hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), the understanding of GDF15 biology following bariatric surgery remains limited [14, 15]. In one study in individuals with obesity, GDF15 concentrations increased upon oral glucose tolerance test; however, GDF15 response to meal tolerance test (MTT) is unknown [16].

In contrast, data on circulating cortisol, a stress hormone released by the adrenal glands, are abundant but with mixed results as it relates to weight gain in the general population. Glucocorticoid (GC) exposure, as in Cushing Syndrome, is associated with weight gain, leading to accumulation of visceral fat and obesity [17–19]. In addition, several studies showed that plasma cortisol rises rapidly after a meal in healthy individuals [20, 21]. Interestingly, individuals with obesity display lower circulating cortisol concentrations compared to individuals with normal weight [22, 23]; however, cortisol response to MTT is not well understood [23]. There is evidence in hypothalamic–pituitary–adrenal axis dysfunction [24], obesity [23], or after bariatric surgery [25].

Therefore, we aimed to examine the stimulated GDF15 and cortisol response among individuals with versus without weight regain after sleeve gastrectomy. Given that GDF-15 is a satiety hormone that is associated with weight loss after bariatric surgery and cortisol dysfunction is associated with obesity, we hypothesized that GDF-15 and cortisol response to meal stimulation will be attenuated in individuals with versus without weight regain after sleeve gastrectomy.

Methods

Study Population

This is a cross-sectional study of 21 adults who underwent sleeve gastrectomy (SG) from 2009 to 2014 at a single tertiary academic center. Participants were recruited for a parent study aimed to understand post-bariatric surgery hypoglycemia and included adults without diabetes. We excluded anyone with history of other gastrointestinal surgery, pancreatitis, chronic illnesses; use of oral steroids within 2 months prior to screening, or frequent alcohol use. The Johns Hopkins Institutional Review Board approved this study and informed consent was obtained from each participant.

Demographic and Clinical Characteristics

Demographic and relevant clinical data were collected from participants and confirmed by electronic chart review. Weight regain, the primary outcome, was defined as 100 × (current weight − nadir)/(preoperative weight − nadir) > 10% based on previous studies [26, 27].

Meal Tolerance Test

After an overnight fast, participants underwent meal tolerance tests the next morning by drinking a can of Ensure Plus High Protein (Abbott Nutrition, Abbott Park, IL, USA) 6 ml/kg [(maximum 360 ml), content per 100 ml: carbohydrate 15.9 g, protein 7.9 g, fat 3.3 g, energy 125 kcal] within 15 min. Participants underwent blood sampling at the following time points: 0, 15, 30, 45, 60, 90, 120, 180, 240 min with 0 min marking the beginning of the meal. All blood samples were stored at − 80 °C until analysis.

Assays and Measures

Plasma glucose was measured using the hexokinase G-6-PDH method (Beckman Coulter, Brea, CA). Plasma hormones were measured by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA): insulin (ELISA; Mercodia, Winston Salem, NC; intra-assay variation 2.8–4.0%; inter-assay variation 2.6–3.6%); cortisol (RIA; MP biomedicals, LLC, Solon, Ohio, intra-assay 5.0% and inter-assay coefficient variation 7.4%); GDF15 (ELISA; R&D systems, Minneapolis, MN: catalog no: DGD150, intra-assay 1.8–2.8% and inter-assay variation 4.7–5.6%); GIP (ELISA; Millipore, Billerica, MA; intra-assay variation 3.0–8.8%; inter-assay variation 1.8–6.1%); and total GLP-1 (ELISA; Alpco Diagnostics, Salem, NH; intra-assay variation 3.7–4.7%; inter-assay variation 6.2–9.5%). The homeostasis model assessment of insulin resistance (HOMA-IR) was used to determine insulin sensitivity and was calculated as follows: fasting insulin (μU/mL) × fasting glucose (mmol/L)/22.5 [28]. The area under the curve (AUC) was calculated for GDF15 and cortisol using the trapezoidal rule and was used as a proxy of the amount of GDF15 and cortisol in the circulation or hormones secreted.

Statistical Analysis

Analysis

We used independent t-tests for continuous variables, and Fisher’s exact tests for categorical variables to compare participant baseline characteristics between the WR and non-WR groups.

Wilcoxon signed-rank tests were used to assess paired within-person changes in GDF15 and cortisol during the MTT relative to 0 min stratified by WR status; Wilcoxon rank-sum tests compared AUCs of GDF15 and cortisol between the WR and non-WR groups. For each hormone (GDF15 and cortisol), we computed three tests of AUC: AUC from 0 to 240 min, AUC from 0 to 60 min (early response), and AUC from 60 to 240 min (late response). As a secondary analysis, we also performed Wilcoxon signed-rank tests to assess paired within-person changes in secondary outcomes: glucose, insulin, total GLP-1, and GIP during the MTT relative to 0 min stratified by WR status. All statistical analyses were performed using the STATA version 13 software. p-values (p) < 0.05 were considered statistically significant.

Results

Baseline Characteristics

Baseline characteristics of the participants are shown in Table 1; fifteen of the 21 patients (71%) had regained > 10% of the weight lost. Among all participants, 48% were Caucasian, 85% were female, mean ± SD age was 43 ± 10 years, and mean ± SD BMI was 36.2 ± 7.6 kg/m2, and the median (range) 3(3–6) number of years since bariatric surgery. Participants with WR had BMI (38.6 ± 7.6 kg/m2) with higher mean HOMA-IR, although it was not statistically significant compared to those without WR following bariatric surgery (Table 1).

Table 1. Patient characteristics.

Characteristics All population Non-weight regainers Weight regainers p-value
Participants (n) 21 6 15
Age (years) 43 ± 10 46 ± 11 42 ± 9 0.40
Sex, female (%) 85 100 80 0.24
Race, White*(%) 48 33 53 0.12
Preop, weight (lbs) 304.3 ± 66.3 292.7 ± 22.1 308.9 ± 66.3 0.57
Preop, BMI (kg/m2) 47.6 ± 5.9 46.6 ± 5.5 47.9 ± 6.2 0.66
Weight nadir (lbs) 212.0 ± 54.6 194.0 ± 26.3 219.8 ± 62.2 0.35
Current weight (lbs) 233.8 ± 61.8 197.2 ± 34.7 248.4 ± 65.0 0.08
Current BMI (kg/m2) 36.2 ± 7.6 30.3 ± 3.5 38.6 ± 7.6 0.02
Weight gain (%) 28.2 ± 25.8 4.3 ± 8.9 37.8 ± 24.1 0.004
Time since surgery (years, range) 3(3–6) 3.5(3–4) 4(3–6) 0.20
HOMA-IR 0.66 ± 0.51 0.35 ± 0.32 0.78 ± 0.53 0.08
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Values are expressed as mean ± SD, median (range).

*

The population race is White or Black.

Bold represents p ≤ 0.05. Weight regain is defined by > = 10% as calculated by 100 × (current weight − nadir)/(preoperative weight − nadir). Abbreviations: preop, preoperative; BMI, body mass index; surg, surgery; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; AUC, area under the curve

Meal-Stimulated GDF15 and Cortisol Response

The fasting GDF15 and cortisol concentrations were similar in the WR and non-WR groups. After MTT, the overall GDF15 response was significantly lower in the WR group as shown by the AUC(0–240 min) 116143 ± 13973 ng*min/L compared to non-WR group AUC(0–240 min) 185798 ± 38884 ng*min/L, p = 0.047 (Fig. 1A). The overall cortisol response was significantly lower in the WR group (AUC 3492 ± 210 μg*min/dL) compared to non-WR group (AUC 4880 ± 655 μg *min/dL, p = 0.015) (Fig. 1B). The GDF15 response between the WR and non-WR groups began to diverge at time 60 min, with significant differences between groups, p < 0.05. Compared to baseline values, there was a significant increase in GDF15 in both groups at 120, 180, and 240 min, p < 0.05, but a slower and more attenuated increase in the WR group (Fig. 1C). After MTT, cortisol concentrations remained flat among the WR group but significantly increased for the non-WR group at 30, 45, 60, and 90 min and significantly declined at 180 and 240 min for both groups compared to baseline values (Fig. 1D). Early GDF15 and cortisol responses (AUC(0–60 min)) were similar between the two groups. However, WR group had significantly lower late GDF15 and cortisol response compared to non-WR group, p < 0.05 (Fig. 1E and F).

Fig. 1.

Fig. 1

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Time-course of A GDF15 and B cortisol after MTT (meal tolerance test), C GDF15 AUC(0–240 min) (area under the curve), D cortisol AUC(0–240 min), E GDF15 AUC(0–60 min), compared to GDF15 AUC(60–240 min), F cortisol AUC(0–60 min) compared to cortisol AUC(60–240 min), late response among WR group (weight regain ≥ 10%) compared to without WR group (weight regain < 10%). Data are means ± s.e.mean of (N) individuals in each group. Statistical comparison to without WR group (+), baseline or pre-administration values (time 0) (*) is indicated by * + p < 0.05

Secondary Outcomes

The fasting glucose concentrations remained similar between groups through the MTT: WR group AUC(0–240 min) 19925 ± 2166 mg*min/dL vs non-WR group AUC 20616 ± 3128 mg*min/dL, p = 0.63 (Fig. 2A). After MTT, plasma insulin concentrations only increased significantly changed in WR group at 15 min and dropped by 90 min, and were significantly different between the groups (WR group AUC(0–240 min) 6289 ± 3432 μU* min/ml vs non-WR group AUC 3025 ± 2089 μU* min/ml, p = 0.04) (Fig. 2B). Both total GLP-1 and GIP response were increased from baseline after MTT in both groups; but no difference was observed between the groups WR group GLP-1 AUC(0–240 min) 2013 ± 577 pM*min vs non-WR group GLP-1 AUC(0–240 min) 1631 ± 627 pM*min (Fig. 2C) and WR group GIP AUC(0–240 min) 51744 ± 5276 pM*min vs non-WR group GIP AUC(0–240 min) 49,663 ± 10117 pM*min (Fig. 2D).

Fig. 2.

Fig. 2

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Time-course of A plasma glucose, B plasma insulin, C total GLP-1, and D GIP after MTT (meal tolerance test) among WR group (weight regain ≥ 10%) compared to without WR group (weight regain < 10%). Data are means ± s.e.mean of (N) individuals in each group. Statistical comparison to without WR group (+), baseline or pre-administration values (time 0) (*) is indicated by * + p < 0.05

Discussion

To our knowledge, this is the first study reporting meal-stimulated GDF15 and cortisol responses in individuals with weight regain (WR) after (SG). We hypothesized that GDF15 and cortisol response to MTT would be diminished in SG patients with weight regain compared to those who did not regain weight given the anorexic role of GDF15 [5] and the association of flat diurnal cortisol curves and low cortisol concentrations with hypothalamic–pituitary–adrenal dysfunction [24] and obesity [23]. Therefore, the relatively lower concentrations of these two hormones may lead to WR.

We found that individuals with WR had lower GDF15 and cortisol response after MTT compared to non-WR group. While the overall response curves of these hormones clearly differed between the WR and non-WR groups, only the late phase (60–240 min) was significantly different between the two groups. The lack of statistical difference in the early phase (0–60 min) and fasting state for GDF15 and cortisol between the two groups is likely driven by small sample size and because the estimated differences at baseline were small; this should be further evaluated. In regard to the shape of the hormonal response curves, concentrations for both hormones tended to be lower and the response curves were flatter and blunted among the WR group compared to non-WR group. These results are in agreement with known lower concentration of these hormones in obesity [5, 23]. In addition, the response of the non-WR group best match with well-characterized intact cortisol response associated with normal subjects [21].

It has been reported that GDF15 is unchanged acutely after a meal or a glucose load in healthy humans [5]. However, our results showing that circulating GDF15 concentration increased in all individuals in the late response phase of MTT (60–240 min) mirrored similar results from a study performed in individuals with obesity showing that oral glucose tolerance test increased circulating GDF15 concentration in the late response phase of the test (90–180 min) [16]. Taken together, our study suggests that the main response of these two hormones happens in the late phase and that a more robust GDF15 response to MTT may be associated with more favorable weight outcome after SG among people with obesity. In fact, previously bariatric surgery studies among individuals measured at 12 months and 2.5–4 years following SG [14] or Roux-en-Y gastric bypass [13], respectively showed that weight loss is correlated with an increase in fasting GDF15 following bariatric surgery.

This study provided further characterization of GDF15 secretion after a meal among individuals with obesity since the timing in which the GDF15 is secreted after a meal is understudied. In addition, the exact mechanism accounting for the difference in GDF15 response between the WR group compared to non-WR group is unknown. Pre-clinical studies have reported that GDF15 administration reduced appetite and triggers taste aversion via the activation of the GDF15 receptor (GFRAL) [5]. However, we cannot confirm a reduction in food intake in this study, and this would be important for future clinical studies.

We know that circulating GDF15 concentration is altered by multiple factors including stress, diet, obesity, and surgery not only by food intake [29]; interestingly, animal data shows that elevated GDF15 can be dissociated from food intake [30]. The mechanisms by which both bariatric surgeries [13] and sleeve gastrectomy [14] inherently increase GDF15 are unknown. GDF15 is expressed in most tissues including the liver [5] and adipose tissue [31]. It is hypothesized that perhaps, the recalibration of energy metabolism in the tissues after bariatric surgery and the increase in physical activity in people with obesity after bariatric surgery may be factors contributing to the increase of GDF15; however, these hypotheses need to be further investigated.

Another potential explanation to the increase in GDF15 is that GDF15 is regulated by cortisol. In this study, the regulation may occur in the late response phase when GDF15 increased, perhaps as a response to the decline in cortisol. Our results showed that the significantly blunted GDF15 response in WR group compared to non-WR group started at the time cortisol response reached its peak and started to decline. In support of this idea, two in vitro studies have reported the reduction of GDF15 gene expression by glucocorticoids [32, 33]. Also, a recent study showed that GDF15 is elevated in conditions of glucocorticoid deficiency and reduced upon glucocorticoid replacement (hydrocortisone) [34]. How this regulation occurs is still unknown. Also, it is plausible that the GDF15 and cortisol differences are the effect of weight gain and not the mechanism behind weight gain; however, this is also a speculation that needs further investigation.

Given that the WR group had a higher meal-stimulated insulin response and were more insulin resistant compared to non-WR group, it is unlikely that insulin affects GDF15 which has been reported in some studies [5, 16]. Another interesting finding from our study is that attenuated meal-stimulated cortisol response seen in WR group is associated with insulin resistance. It has been suggested in an epidemiological study that higher cortisol concentrations are associated with decreased insulin secretion [35] and sensitivity [36]; also, in vivo experiments on cultured ß-cells in mice have shown that direct glucocorticoid suppressed insulin secretion [37]. However, acutely, it has also been shown hyperinsulinemia causes activation of HPA axis and increases serum cortisol concentration in healthy men [38]. Nonetheless, the direct effects of glucocorticoids on insulin secretion remain to be fully elucidated in humans.

In addition, based on our results, it seems that GDF15 response in WR group is not associated with changes in plasma glucose or incretins (GLP-1 and GIP) response. This could imply that GDF15 activation and incretins may act via different systems. It has been shown recently in mice that GDF15 and GLP-1 receptor agonist engage in separate anorexic neuronal systems to produce weight loss [39].

This study has both strengths and limitations. Regarding study strengths, the study had a well-characterized population with multiple weight measurements over several years. Another strength is in the use of meal tolerance test to stimulate the post-prandial of stress hormones and measurement of fasting hormones in the morning across all participants given the importance of diurnal pattern hormonal secretions. Our study was cross-sectional which did not allow to explain causality, whether the hormones play a role in the weight regain or if it is the weight regain that impacted hormonal response. We lacked information on dietary and exercise habits and on the assessment of preoperative hormonal response to MTT. We had a limited sample size of individuals who are mostly women and all post-sleeve gastrectomy. Nonetheless, our study is representative of the current bariatric population as the most widely performed bariatric procedure in the USA is sleeve gastrectomy and more women than men undergo this type of surgery [40].

Conclusion

This study showed lower GDF15 and cortisol responses to a meal tolerance test among patients who regained weight after sleeve gastrectomy compared to those who did not. Taken together, a dysfunction in GDF15 pathway and cortisol axis may help explain the underlying differences of weight regain after bariatric surgery. Future studies are needed to examine the exact mechanistic link between GDF15 and cortisol, glucocorticoid receptors, and its potential therapeutic role in obesity management.

Key Points.

  • GDF15 and cortisol are stress hormones known to be associated with weight change.

  • MTT GDF15 and cortisol response after SG among WR was lower compared to non-WR.

Acknowledgements

Authors are most grateful to participants in this study and to Dr. Sherita H. Golden and Dr. Gary Wand for their advice. JPD performed part of this work as a special volunteer at NIA, National Institute of Health.

Funding

Dr. Lee was supported by grant K23 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Dr Brown is supported in part by K24 AI120834. Dr. Shardell was supported by NIA grants R01 AG048069, R56 AG068673, R03 AG070178, and P30 AG028747-15S1. CJL was supported by a career development award from the NIH/NIDDK (K23DK107921).

Footnotes

Conflict of Interest The authors declare no competing interests.

Ethics Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to Participate Informed consent was obtained from all participants included in the study.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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