Fibroblast growth factor 21 (FGF21) is increased in MDD and interacts with body mass index (BMI) to affect depression trajectory

Brittany L. Mason,Madhukar H. Trivedi,Abu Minhajuddin,Andrew H. Czysz,Manish K. Jha,Taryn L. Mayes,Bharathi S. Gadad

doi:10.1038/s41398-021-01679-y

Abstract

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolic function and nutrient preference. It also affects biological pathways associated with major depressive disorder (MDD), including corticotrophin-releasing hormone (CRH), leptin, and sympathetic activity. Lower levels of cerebrospinal fluid FGF21 have been associated with higher Beck Depression Inventory scores. FGF21 was examined as a metabolic marker that could be associated with MDD and evaluated as a biomarker of antidepressant treatment response in a large, randomized placebo-controlled trial in chronic, early-onset MDD participants. FGF21 levels at baseline and during treatment were determined for participants in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. FGF21 was analyzed by ELISA in individuals with chronic, early-onset MDD (first major depressive episode before 30 years) compared to healthy control participants. Participants with MDD had higher levels of FGF21 compared to healthy controls (HCs), even after controlling for baseline age, sex, race, Hispanic ethnicity, BMI, and site (β-coefficient = 1.20, p < 0.0001, Cohen’s d = 0.60). FGF21 did not change over time nor differ between treatment groups. Interestingly though, those with normal BMI and lower FGF21 levels showed a reduction in depression severity over time compared to all other groups. In conclusion, depression is associated with higher levels of FGF21 compared to healthy controls and those with lower levels of FGF21 (25th percentile of the sample) in the context of normal-weight BMI seem to have improved depression severity over time.

Highlights

Obesity and associated metabolic dysfunction have been shown to significantly impact the biology, disease course, and treatment response of major depressive disorder (MDD) [1, 2], and yet the basic mechanisms underlying these associations are largely underrecognized
Fibroblast growth factor 21 (FGF21) is associated with poor metabolic health, with serum FGF21 levels being positively correlated with adiposity, fasting insulin and triglycerides, and increased risk of metabolic syndrome associated with high FGF21 [5]
FGF21 was not associated with stress-induced increase in cortisol in humans 3 months following a period of chronic stress, but was positively correlated with self-reported ability to cope with the stress [7], suggested that FGF21 may play a role in managing the consequences of psychological stress

Summary

Introduction

Obesity and associated metabolic dysfunction have been shown to significantly impact the biology, disease course, and treatment response of major depressive disorder (MDD) [1, 2], and yet the basic mechanisms underlying these associations are largely underrecognized. FGF21 is associated with poor metabolic health, with serum FGF21 levels being positively correlated with adiposity, fasting insulin and triglycerides, and increased risk of metabolic syndrome associated with high FGF21 [5]. This increased risk in the context of higher adiposity may be related to FGF21 resistance, which has been demonstrated in obese mice having significantly reduced FGF21 signaling response in both liver and fat tissues following exogenous administration of FGF21 [6]. There are fewer data to support how FGF21 may be related to psychiatric conditions that involve psychological stress, such as MDD

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