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Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic

Soyoung Park1, Alice Jang1, Sebastien G Bouret2,3

  • 1The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, Los Angeles, California, United States of America.

Plos Biology
|March 13, 2020
PubMed

Insights

Maternal obesity in mice programs offspring for metabolic disease via endoplasmic reticulum (ER) stress. Early life ER stress intervention reversed these deficits, highlighting a critical developmental window for preventing obesity and type 2 diabetes.

Area of Science:

  • Metabolic disease
  • Developmental biology
  • Endocrinology

Background:

  • Rising rates of childhood obesity and type 2 diabetes mellitus present a significant public health challenge.
  • Maternal obesity is a key risk factor for metabolic dysfunction in offspring.
  • Endoplasmic reticulum (ER) stress is implicated in leptin resistance and type 2 diabetes.

Purpose of the Study:

  • To investigate the role of early life ER stress in the developmental programming of metabolic disease in offspring from obese mothers.
  • To examine the impact of maternal obesity on offspring metabolic parameters and neurodevelopmental pathways.

Main Methods:

  • Utilized a mouse model of maternal obesity.
  • Assessed offspring for glucose intolerance, body weight, adiposity, and food intake.
  • Analyzed hypothalamic melanocortin circuits and ER stress-related gene expression.
  • Investigated the therapeutic effect of tauroursodeoxycholic acid (TUDCA) on metabolic and neurodevelopmental deficits.

Main Results:

  • Offspring of obese dams exhibited glucose intolerance, increased body weight, adiposity, and food intake.
  • Maternal obesity led to disrupted melanocortin circuits, neonatal hyperleptinemia, and leptin resistance.
  • ER stress markers were elevated in the hypothalamus of neonates from obese mothers.
  • Neonatal TUDCA treatment ameliorated metabolic and neurodevelopmental issues and reversed leptin resistance.

Conclusions:

  • Early life endoplasmic reticulum stress, induced by maternal obesity, contributes to the developmental programming of metabolic disease in offspring.
  • Targeting ER stress during the neonatal period offers a potential therapeutic strategy to prevent or reverse obesity and type 2 diabetes-related complications.
  • Intervention with ER stress-relieving agents like TUDCA can improve metabolic health and neurodevelopmental outcomes in offspring exposed to maternal obesity.

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