Effect of acute and long-term exercise on leptin levels in depressed outpatients

doi:10.21203/rs.3.rs-2582531/v1

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Effect of acute and long-term exercise on leptin levels in depressed outpatients

https://doi.org/10.21203/rs.3.rs-2582531/v1

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Background: Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.

Methods: Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.

Results: Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.

Conclusion: Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.

depression

leptin levels

exercise

body fat

On a global scale, the World Health Organization (WHO) estimates that 5% of adults live with depression, a leading cause of disability worldwide and a significant contributor to the global burden of disease [1]. The number of patients with depression increased by 18.4% between 2005 and 2015, which is a significant increase compared to other mental illnesses [2]. In addition, the emergence of the COVID-19 pandemic has created an environment where many determinants of poor mental health are even exacerbated [3]. The persistent and ubiquitous nature of depression, coupled with its penchant to drive disability, morbidity, and mortality indicate the pressing need to develop innovative and broadly effective interventions [4]. The clinical prescription of antidepressant drugs remains the most common treatment for patients with depression, although typical antidepressants have various limitations in terms of therapeutic efficiency and onset time [5, 6]. Thus, other non-pharmacological and unconventional treatments, such as exercise, have been widely recommended due to their safety and non-toxic side effects [2]. Both the WHO [7] and the NICE guidelines (National Institute for Health and Care Excellence 2022) recommend implementing physical exercise in the standard treatment of depression. Based on systematic reviews and meta-analyses findings, exercise has an anti-depressant effect and even potential protective benefits [9–15]. The SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients), a randomized controlled trial performed by our group, showed that a 12-week endurance exercise program with high intensity leads to an improvement in physical fitness compared to an endurance exercise program in low intensity and to a waiting list control group, while depressive symptoms improved in all groups [16, 17].

The multifactorial pathophysiology of depression, including disrupted neurogenesis, genetic susceptibility, and metabolic disturbance, complicates prediction and actual individual treatment rates [18]. Recent studies suggested an association between leptin dysregulation and depression, possibly through brain neurogenesis pathways [19, 20]. As proposed in several basic studies, leptin has antidepressant effects and might be a potential therapeutic target for depression [21]. Leptin is one of the major hormones responsible for controlling energy balance and body weight by altering energy intake and energy expenditure [22, 23]. Leptin receptor (LepRb) deficiency leads to memory and cognitive impairments that are accompanied by alterations in hippocampal synaptic plasticity [24]. Acute administration of leptin has been reported to have antidepressant and anxiolytic effects in mice [25]. However, studies investigating the relationship of major depressive disorders (MDD) and leptin levels have yielded somewhat discrepant results. Initial studies reported lower leptin levels in depressive patients compared to healthy controls, which coincided with initial reports of leptin’s antidepressants effects in animal models [26–29]. Nevertheless, higher leptin levels in MDD have also been reported [30, 31]. Beyond that, it is unclear whether endurance exercise changes leptin levels and can be used as a potential therapeutic option. Therefore, in the current sub-project of the SPeED study, we aimed to investigate whether (i.) depressed patients have altered leptin levels compared to healthy controls, (ii.) acute and/or long-term endurance exercise influences leptin levels and (iii.) the intensity of the training determines the change in leptin.

3.1 Participants and eligibility criteria

105 out of 113 participants of the original SPeED study [16,17] with a diagnosis of mild to moderate depression were included (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0; range: 22-66 years) and compared to 34 healthy controls at baseline (t1) (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0; range: 21-60 years). Participants were recruited between 07/23/2015 and 12/11/2019 and randomly assigned to one of three groups: high intensity exercise group (HEX), low intensity exercise group (LEX), and a waiting list control group (WL). All Participants, MDD and HC, passed a sport medical examination and were excluded with a current severe depressive episode with or without psychotic symptoms, the use of benzodiazepines or beta-blockers within the last 7 days, or tricyclic antidepressants and neuroleptic drugs with a dose of > 40% of the cumulated maximum recommended daily dose, a body mass index of > 35 or < 18, and more than 90 min of physical exercise per week (for detailed information on inclusion and exclusion criteria see [16]). The study protocol was approved by the local ethics committee of Charité Universitätsmedizin Berlin, Germany (No EA1/113/15) and the ethics committee of the Freie Universität Berlin, Germany (No 133/2016). Written informed consent was obtained from all participants.

3.2 Procedure

Sport medical examination - To assess eligibility on the one hand and the effect of exercise on the other hand, all participants had to pass a sport medical examination, which included a graded bicycle ergometer test at baseline (t1) and after a 12-week intervention period (t2). The bicycle test was monitored by electrocardiogram. Heart rate, blood pressure, and lactate levels were assessed before starting the test, at the end of each resistance level, and after completion. The test started at 25 W with a graded increase in power of 25 W every 2 min until reaching the maximal physical exertion or the occurrence of general termination criteria according to the Borg scale [32]. See Kallies et al. [33] and Heinzel et al. [17] for further details of the physical fitness and physical activity assessment.

Intervention - The SPeED study was applied as a longitudinal design. To assess long-term training effects on leptin levels in depression the MDD group received a 12-week endurance exercise program. The MDD participants were randomly assigned to three groups: two exercise intervention groups (EX) took part in a 12-week exercise program and were compared to a waiting list control group (WL). The exercise groups received supervised endurance exercise training following the guidelines of the American Heart Association for endurance exercise [34], differing in their intensities. In the HEX group, one session included a 20-min bicycle ergometer, 20-min running or Nordic walking, and 20 min of aerobic body workout at approximately 55%-85% of the individual maximum heart rate reserve. The LEX group received a similar exercise program, with the distinction of a 20-min bicycle ergometer, 20-min walking, and 20-min stretching and relaxation of about 20%-30% of the individual maximum heart rate reserve. Each session was constantly monitored by electrocardiogram (ECG), measurements of blood pressure, lactate, and Borg’s rating scale of perceived exertion (RPE, (Borg, 1982)) before starting the test, at the end of each level, at maximum exhaustion, as well as three and five minutes post exercise [16].

3.3 Measures

Depression - The severity of depression was measured by the German version of the Beck Depression Inventory 2 (BDI-2; [35]. The BDI-2 consists of 21 items rated on a 4-point Likert scale ranging from 0 (non-existent) to 3 (strong expression). With a total score ranging from 0-63, the BDI-2 is a self-report instrument that classifies the severity of depression into the following categories according to the BDI-2 manual of Beck et al. (1996): a score of 0-13 indicates minimal depression, 14-19 mild depression, 20-28 moderate depression, and 29-63 severe depression. With a Cronbach´s α = 0.81 the reliability in the present study showed good internal consistency.

Blood samples - Serum levels of leptin were measured prior to and after the bicycle ergometer tests at baseline (t1) in all participants and after the 12-week intervention period (t2) in the exercise groups and waiting list control group. To quantify leptin venous blood samples were drawn from the antebrachial vein after a rest period of at least 20 min (pre-exercise) and post-exercise samples were collected within 5 min after completion of the bicycle ergometer test. Blood was allowed to clot for 60 min at room temperature before centrifugation at 1,300 × g and 20 °C for 10 min. Until analyzation, the resulting serum fraction was aliquoted into microliter tubes and stored at -30 °C. For leptin measurements, an enzyme-linked immunosorbent assay (ELISA) method was performed using the Human Leptin Quantikine ELISA Kit (DLP00) from Biotechne (R&D Systems Inc., a Bio-Techne Brand, Minneapolis, Minnesota, United States.

3.4 Statistical analysis

All data were processed and statistically analyzed using SPSS 28 (IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp). Continuous data are summarized as mean and SEM. The Shapiro-Wilk test was used to test for the normal distribution of variables. For correlation analysis, Pearson´s correlation test was used. Repeated measures ANOVA (rmANOVA) and paired sample t-test were applied to compare the mean levels before and after the bicycle ergometer test as well as before and after the intervention period. Differences were considered significant at p < 0.05 for all tests. Sensitivity analysis were performed by using an ANCOVA model to test phenotypic traits as covariates in exercise induced leptin alterations.

The present sub-project of the SPeED study aimed to investigate the difference in circulating leptin levels between depressed patients and healthy controls and to examine the impact of acute and long-term endurance exercise on leptin levels.

Baseline characteristics - Within the presented sub-project of the SPeED study, 105 patients with major depressive disorder (MDD) were compared with 34 healthy controls (HC) as reported in the flow chart in Fig. 1. At baseline, the HC and MDD group had comparable anthropometric characteristics (Fig. 2A) including the phenotypic traits body weight (72.2 ± 2.4 vs. 75.4 ± 1.6; p = 0.296), body fat (18.9 ± 0.9 vs. 17.9 ± 0.8; p = 0.589), percent body fat (25.6 ± 1.7 vs. 23.1 ± 0.8; p = 0.163) as well as a similar body mass index (BMI) (24.6 ± 0.7 vs. 24.7 ± 0.4; p = 0.929). Depressive symptoms (BDI-2) were significantly higher in the MDD group (0.82 ± 0.27 vs. 27.08 ± 0.77; p < 0.001) (Fig. 2B).

In the current study, bivariate correlation analyses also showed a positive correlation between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043). Given the numerical difference in the magnitude of the association between depressed patients and healthy controls, we calculated a z-test to determine whether the association between body weight and leptin levels was attenuated in depressed patients, but this difference proved not be significant (z = 1.46, p = 0.14). For the percentage of body fat, we found an even stronger correlation of equal magnitude in both groups, HC and MDD (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001) (Fig. 2C). Similarly, no difference in leptin levels was detected between patients with depression and healthy controls (HC: 12.43 ± 1.89 vs. MDD: 10.91 ± 1.05) (Fig. 2D, left panel). The subdivision of the individual groups according to gender showed, as expected, significantly higher values for women than for men, but again independent of the depression status (Fig. 2D). In conclusion, circulating leptin levels were not altered in patients with major depression compared to healthy controls.

Effects of acute exercise - To test whether leptin levels change after a single bout of exercise and were dependent on the depression status, all participants performed a bicycle ergometer test. As shown in Fig. 3A, the change of leptin levels (Time: F(1,137) = 1.678, p = 0.197, partial η² = 0.012, Time*Group: F(1,137) = 0.534, p = 0.466, partial η² = 0.004) was not significantly different between pre- and post- acute exercise and not different between MDD patients and healthy controls, showing that the bicycle ergometer test had no effect on the change in leptin levels, nor that the response was altered in depression.

Long-term effects of endurance exercise - All MDD patients were randomly allocated to one of three groups; a low-intensity (LEX) or a high-intensity (HEX) endurance exercise group (EX) or a waiting list control group (WL) (Fig. 1). Overall, the comparison of EX and WL revealed a marginally significant main and significant interaction effect (Time: F(1,65) = 3.176, p = 0.079, partial η² = 0.047; Time*Group: F(1,65) = 4.474, p = 0.038, partial η² = 0.064). In contrast to the exercise group with similar leptin levels pre- and post-exercise intervention, leptin levels of the waiting group, which were higher at baseline, decreased after 12 weeks (Fig. 3B). Body weight (Time: F(1,65) = 0.381, p = 0.144, partial η² = 0.033; Group*Time: F(1,65) = 0.381, p = 0.539, partial η² = 0.006) and percent of body fat (Time: F(1,65) = 0.497, p = 0.483, partial η² = 0.008; Group*Time: F(1,65) = 0.004, p = 0.948, partial η² = 0.000) were not different between the groups pre and post exercise intervention (Fig. 3C), but body fat content was numerically higher in the WL than in the exercise groups (Fig. 3C). Furthermore, the WL group showed a sizeable decrease in body fat at baseline (t1, Fig. 1C) and this initial difference in body fat between WL and EX groups may explain the higher leptin levels in the WL at baseline as well as the subsequent stronger decrease in leptin levels over time. An independent sample t test revealed a statistically significant difference in percent of body fat at baseline between EX and WL, t(28.05) = -2.155, p = .040*. Since a considerable interaction effect of group membership on the leptin levels was observed, a possible impact of percent of body fat on the change in leptin levels was investigated by using an ANCOVA, taking leptin levels before and after the intervention as dependent variables, the group’s membership as the fixed factor and body fat as a covariate. The ANCOVA revealed that the interaction of the change in leptin levels and group membership was no longer significant when taking body fat as covariate, Time: F(1,64) = 0.044, p = 0.834; partial η² = 0.001; Time*Body fat: F(1,64) = 0.164, p = 0.687 partial η² = 0.003; Time*Group: F(1,64) = 3.587, p = 0.063, partial η² = 0.053.

In terms of training intensity, results of the rmANOVA considering leptin levels showed no significant changes indicating that there was no overall effect of exercise on leptin levels and this is independent of the exercise intensity (Time: F(1,45) = 0.150, p = 0.701, partial η² = 0.003; Time*Group: F(1,45) = 2.117, p = 0.153, partial η² = 0.045). However, the concentration of leptin levels decreased numerically in the HEX group, while the levels increased in the LEX group (Fig. 3D, left panel).

Studies investigating the relationship between major depressive disorder (MDD) and leptin levels revealed conflicting results, and it is so far unclear whether endurance training alters leptin levels. Therefore, within the sub-project of the SPeED study, circulating leptin levels of patients with depression were compared with healthy controls before and after an acute exercise bout and long-term exercise intervention. Overall, leptin levels were not altered in patients with major depression compared to healthy controls, and exercise, both acutely and after 12-week endurance training, had no effect on the change in leptin levels. The training intensity showed no significant differences in the effect of exercise on serum leptin.

Besides the role of leptin regulating energy homeostasis, in which it acts as a negative feedback adiposity signal by interacting with receptors in specific hypothalamic nuclei, growing experimental results indicate that leptin also plays a significant role in other areas of the central nervous system (CNS) and is associated with several pathological and physiological mechanisms of neurological diseases, including neurodegenerative diseases and mood disorders [36, 37]. Leptin influences neurotransmitters such as dopamine [38] and impacts gray matter plasticity [39]. It was found that neurological diseases occurred alongside leptin level alterations, indicating that leptin might be a critical modulator of these diseases, and studying the specific relationship is of significance [40]. Available information about the role of leptin signaling in human depression is limited and controversial. Similar to our findings, the first study analyzing plasma leptin concentrations in depressed patients reported no difference between depressed patients and healthy controls, despite a weight loss in the patients examined [41]. Nevertheless, several clinical studies have found lower serum leptin levels in individuals with MDD compared to healthy controls [26, 28], whereas other data in women with MDD revealed significantly increased plasma leptin levels [30, 31, 42]. Similarly, some studies reported that leptin concentrations are variously increased [30, 43] or not changed by antidepressant treatment [43, 44]. Lastly, some studies suggest that leptin may be a biomarker of risk for de-novo depression [45, 46]. One possible explanation for the seemingly contradictory data may be that leptin levels are influenced by certain factors such as age, sex, body mass status, medication history, and comorbidity with other disorders [21]. Another interpretation is that leptin insufficiency may only occur in a subpopulation of depressed patients [47]. The systematic review and meta-analysis by Carvalho et al. underscore that relevant moderators/confounders (e.g., BMI, depression severity, and type of assay) should be controlled for when considering the role of leptin as putative MDD diagnostic biomarker [46].

In the current study, as expected serum leptin levels were positively associated with body weight and even more with body fat content and, moreover, differed depending on sex. The difference in leptin concentrations between men and women is due to body fat, BMI, and the action of sex hormones [48–50]. Luukkaa et al. showed an inverse relationship between testosterone and leptin concentrations. But nevertheless, also the subdivision into women and men revealed no difference regarding leptin levels and the status of depression in the current study [51].

While it stands to reason that exercise and physical activity affect energy balance, the effects of endurance exercise on plasma leptin are somewhat inconsistent. Long-term exercise training resulted in decreased circulating leptin levels, but these reductions were largely driven by improvements in body composition [52, 53]. Although a decrease in percent body fat appears to be one of the most significant factors associated with a decrease in leptin levels, several chronic exercise interventions also reported a decrease regardless of body weight loss [54–56]. Studies examining the leptin response to single bouts of exercise have produced equivocal results, but it appears that circulating leptin levels are only decreased by bouts of exercise with considerably high intensity [57] and long duration [58–61]. Controversially, the results of the current study, with a 12-week exercise intervention, do not show a reduction in leptin levels after acute and long-term exercise. Moreover, in terms of training intensity, no significant differences could be found, although there is a numerically tendency showing that leptin values decreased after a high intensity exercise training while levels increased after a low intensity exercise training. It is possible that putative leptin resistance is positively affected by the training without changing circulating leptin concentrations. An improved leptin sensitivity may contribute to a reduction in depression. Compared to similar levels pre and post intervention in the exercise group, serum leptin decreased in the waiting list control group. However, this difference can most likely be attributed to a higher body fat percentage in the control group before the intervention and a tendency towards reduced body fat and weight after 12 weeks.

In summary, and referring to the initial research questions, the sub-project of the SPeED study showed that (i.) depressed patients had similar leptin levels compared to healthy controls, (ii.) no change in circulating leptin levels after an acute and endurance exercise intervention, and (iii.) the intensity of exercise had no impact on serum leptin in depressed patients.

ANCOVA: Analysis of covariance

BDI-2: Beck Depression Inventory 2

BMI: Body mass index

CNS: Central nervous system

ELISA: Enzyme-linked immunosorbent assay

HC: Healthy controls

HEX: High intensity exercise group

LepRb: Leptin receptor

LEX: Low intensity exercise group

MDD: Major depressive disorder

NICE: National Institute for Health and Care Excellence

rmANOVA: Repeated measures analysis of variance

SEM: Standard error of the mean

SPeED: Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients

WHO: World Health Organization

WL: Waiting list control group

Ethics approval and consent to participate

The study protocol was approved by the local ethics committee of Charité Universitätsmedizin Berlin, Germany (No EA1/113/15) and the ethics committee of the Freie Universität Berlin, Germany (No 133/2016). Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed in the present study are available upon request.

Competing interests

None.

Funding

This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG, grants HE7464/2-1 to S.H., FY1/5-1 to T.F., and STR504/6-1 to A.St.), the Dalla Vecchia Foundation on Depression Research (Dalla Vecchia Stiftung Depressionsforschung) to A.H. and S.H, and by grants from the German Ministry of Education and Research and the State of Brandenburg (82DZD00302, H.V.).

Authors' contributions

A.H., S.H., A.S., T.F. and M.R. initiated, designed, and coordinated the study. D.H. and H.V. performed experiments, data analysis and wrote the manuscript. All authors reviewed, edited, and approved the manuscript.

Acknowledgements

We gratefully thank Andrea Teichmann for technical assistance.

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No competing interests reported.

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Effect of acute and long-term exercise on leptin levels in depressed outpatients

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Abstract

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Background

Methods

3.1 Participants and eligibility criteria

3.2 Procedure

3.3 Measures

3.4 Statistical analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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