Leptin's Inverse Association With Brain Morphology and Depressive Symptoms: A Discovery and Confirmatory Study Across 2 Independent Samples

Ye Zhang; Soumyabrata Munshi; Kaiping Burrows; Rayus Kuplicki; Leandra K Figueroa-Hall; Robin L Aupperle; Sahib S Khalsa; T Kent Teague; Yasuyuki Taki; Martin P Paulus; Jonathan Savitz; Haixia Zheng

doi:10.1016/j.bpsc.2024.04.005

Leptin's Inverse Association With Brain Morphology and Depressive Symptoms: A Discovery and Confirmatory Study Across 2 Independent Samples

Biol Psychiatry Cogn Neurosci Neuroimaging. 2024 Apr 16:S2451-9022(24)00105-8. doi: 10.1016/j.bpsc.2024.04.005. Online ahead of print.

Affiliations

¹ Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. Electronic address: zhang.ye.r5@dc.tohoku.ac.jp.
² Laureate Institute for Brain Research, Tulsa, Oklahoma.
³ Laureate Institute for Brain Research, Tulsa, Oklahoma; Oxley College of Health Sciences, The University of Tulsa, Tulsa, Oklahoma.
⁴ Department of Surgery, University of Oklahoma School of Community Medicine, Tulsa, Oklahoma; Department of Psychiatry, University of Oklahoma School of Community Medicine, Tulsa, Oklahoma; Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, Oklahoma.
⁵ Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Department of Geriatric Medicine and Neuroimaging, Tohoku University Hospital, Sendai, Japan; Smart-Aging Research Center, Tohoku University, Sendai, Japan.

PMID: 38631553
DOI: 10.1016/j.bpsc.2024.04.005

Abstract

Background: Major depressive disorder has a complex, bidirectional relationship with metabolic dysfunction, but the neural correlates of this association are not well understood.

Methods: In this cross-sectional investigation, we used a 2-step discovery and confirmatory strategy utilizing 2 independent samples (sample 1: 288 participants, sample 2: 196 participants) to examine the association between circulating indicators of metabolic health (leptin and adiponectin) and brain structures in individuals with major depressive disorder.

Results: We found a replicable inverse correlation between leptin levels and cortical surface area within essential brain areas responsible for emotion regulation, such as the left posterior cingulate cortex, right pars orbitalis, right superior temporal gyrus, and right insula (standardized beta coefficient range: -0.27 to -0.49, p_uncorrected < .05). Notably, this relationship was independent of C-reactive protein levels. We also identified a significant interaction effect of leptin levels and diagnosis on the cortical surface area of the right superior temporal gyrus (standardized beta coefficient = 0.26 in sample 1, standardized beta coefficient = 0.30 in sample 2, p_uncorrected < .05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both major depressive disorder groups (r = 0.14 in sample 1, r = 0.29 in sample 2, p_uncorrected < .05).

Conclusions: The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with atypical depressive symptoms support the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin may exert these effects should be explored further.

Keywords: Adiponectin; C-reactive protein; Cortical surface area; Cortical thickness; Leptin; Major depressive disorder; Sleep problems.