Early life stress exacerbates obesity in adult female mice via mineralocorticoid receptor-dependent increases in adipocyte triglyceride and glycerol content

Jacqueline R. Leachman, Cole Cincinelli, Nermin Ahmed, Carolina Dalmasso, Mei Xu, Eva Gatineau, Barbara S. Nikolajczyk, Frederique Yiannikouris, Terry D. Hinds, Analia S. Loria

Research output: Contribution to journalArticlepeer-review

Abstract

Previously, we have shown that Maternal Separation and Early Weaning (MSEW) exacerbates high fat diet (HF)-induced visceral obesity in female offspring compared to normally reared female mice. Stress hormones such as glucocorticoids and mineralocorticoids are critical mediators in the process of fat expansion, and both can activate the mineralocorticoid receptor (MR) in the adipocyte. Therefore, this study aimed to, comprehend the specific effects of MSEW on adipose tissue basic homeostatic function, and investigate whether female MSEW mice show an exacerbated obesogenic response mediated by MR. Gonadal white adipose tissue (gWAT), a type of visceral fat, was collected to assess lipidomics, transcriptomics, and in vitro lipolysis assay. Obese female MSEW mice showed increased adiposity, elevated 44:2/FA 18:2 + NH4 lipid class and reduced mitochondrial DNA density compared to obese control counterparts. In addition, single-cell RNA sequencing in isolated pre- and mature adipocytes showed a ~9-fold downregulation of aquaglycerolporin 3 (Aqp3), a channel responsible for glycerol efflux in adipocytes. Obese MSEW mice showed high levels of circulating aldosterone and gWAT-derived corticosterone compared to controls. Further, the MR blocker spironolactone (Spiro, 100 mg/kg/day, 2 weeks) normalized the elevated intracellular glycerol levels, the greater in vitro lipolysis response, and the number of large size adipocytes in MSEW mice compared to the controls. Our data suggests that MR plays a role promoting adipocyte hypertrophy in female MSEW mice by preventing lipolysis via glycerol release in favor of triglyceride formation and storage.

Original languageEnglish
Article number120718
JournalLife Sciences
Volume304
DOIs
StatePublished - Sep 1 2022

Bibliographical note

Funding Information:
This study was supported by funds from the National Institutes of Health (NIH)- National Heart, Lung, and Blood Institute R01 HL135158 to ASL, R01 HL135158-S1 to JRL, the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527, and the NIH- National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK121797-01A1 to TDHJ and MU.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Adiposity
  • Early life stress
  • Lipidomics
  • Single cell RNA-seq
  • Spironolactone

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)
  • Pharmacology, Toxicology and Pharmaceutics (all)

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