Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile non-human primates

  1. Jacob E. Friedman1
  1. 1Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  2. 2Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
  3. 3Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  4. 4Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
  1. Corresponding author: Jacob E. Friedman E-mail: jed.friedman{at}


The origins of non-alcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high fat (HF) diet, and the impact of post-weaning healthy diet on mechanisms for NAFLD development in juvenile non-human primate (NHP) offspring at 1 yr of age. Pregnant females on HF diet were segregated as insulin resistant (HF+IR) or insulin sensitive (HF+IS) compared to control (CON) fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and up-regulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways which persist in vitro, and may be an irreversible ‘first hit’ in the pathogenesis of NAFLD in NHP.

  • Received February 18, 2014.
  • Accepted March 28, 2014.

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