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Diabetes. 2014 Aug;63(8):2702-13. doi: 10.2337/db14-0276. Epub 2014 Apr 4.

Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates.

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Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO.
Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR.
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO


The origins of nonalcoholic 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 postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with 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 upregulated 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 that persist in vitro and may be an irreversible "first hit" in the pathogenesis of NAFLD in NHP.

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