TitleEarly life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates.
Publication TypeJournal Article
Year of Publication2014
AuthorsThorn, SR, Baquero, KC, Newsom, SA, Kasmi, KCEl, Bergman, BC, Shulman, GI, Grove, KL, Friedman, JE
JournalDiabetes
Volume63
Issue8
Pagination2702-13
Date Published08/2014
ISSN1939-327X
KeywordsAdipose Tissue, Animal Feed, Animals, Cytokines, Dietary Fats, Fatty Liver, Female, Gene Expression Regulation, Glucose Tolerance Test, Inflammation, Insulin Resistance, Lipid Metabolism, Liver, Macaca, Macrophage Activation, Macrophages, Non-alcoholic Fatty Liver Disease, Pregnancy, RNA, Messenger
Abstract
 

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.

DOI10.2337/db14-0276
Alternate JournalDiabetes
PubMed ID24705404
PubMed Central IDPMC4113070
Grant ListP51-OD-011092 / OD / NIH HHS / United States
P51 OD011092 / OD / NIH HHS / United States
P30 DK048520 / DK / NIDDK NIH HHS / United States
P30-DK-048520 / DK / NIDDK NIH HHS / United States
DP4 GM096850 / GM / NIGMS NIH HHS / United States
UL1 TR000154 / TR / NCATS NIH HHS / United States
R01 DK079194 / DK / NIDDK NIH HHS / United States
K01-DK-090199 / DK / NIDDK NIH HHS / United States
K01 DK090199 / DK / NIDDK NIH HHS / United States
UL1-TR-000154 / TR / NCATS NIH HHS / United States
R24-DK-090964 / DK / NIDDK NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States
R24 DK090964 / DK / NIDDK NIH HHS / United States