Exacerbated obesogenic response in female mice exposed to early life stress is linked to fat depot-specific upregulation of leptin protein expression

Jacqueline R. Leachman, Mathew D. Rea, Dianne M. Cohn, Xiu Xu, Yvonne N. Fondufe-Mittendorf, Analia S. Loria

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Early life stress (ELS) is an independent risk factor for increased BMI and cardiometabolic disease risk later in life. We have previously shown that a mouse model of ELS, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. Therefore, the aim of this study was to investigate 1) whether the short- and long-term effects of HF on leptin expression are influenced by MSEW in a sex-specific manner and 2) the potential epigenetic mechanisms underlying the MSEW-induced changes in leptin expression. After 1 wk of HF, both MSEW male and female mice displayed increased fat mass compared with controls (P < 0.05). However, only MSEW female mice showed elevated leptin mRNA expression in gonadal white adipose tissue (gWAT; P < 0.05). After 12 wk of HF, fat mass remained increased only in female mice (P < 0.05). Moreover, plasma leptin and both leptin mRNA and protein expression in gWAT were augmented in MSEW female mice compered to controls (P < 0.05), but not in MSEW male mice. This association was not present in subcutaneous WAT. Furthermore, among 16 CpG sites in the leptin promoter, we identified three hypomethylated sites in tissue from HF-fed MSEW female mice compared with controls (3, 15, and 16, P < 0.05). These hypomethylated sites showed greater binding of key adipogenic factors such as PPARγ (P < 0.05). Taken together, our study reveals that MSEW superimposed to HF increases leptin protein expression in a sex- and fat depot-specific fashion. Our data suggest that the mechanism by which MSEW increases leptin expression could be epigenetic.

Original languageEnglish
Pages (from-to)E852-E862
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5
StatePublished - Nov 2020

Bibliographical note

Funding Information:
This study was supported by funds from the National Heart, Lung, and Blood Institute (R00-HL-111354 and R01-HL-135158 to A.S.L., R01-HL-135158-S1 to J.R.L.) and the pilot project from the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527 to A.S.L.

Publisher Copyright:
Copyright © 2020 the American Physiological Society.


  • Adverse childhood experiences
  • Early-life stress
  • Leptin
  • Obesity
  • Sex differences
  • Site-specific methylation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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