Maternal High-Fat Diet Persistently Alters Bone Marrow Immune Cell Proportions and Function in a Nonhuman Primate Model

Abstract

Maternal obesity is rapidly increasing in prevalence and predisposes offspring to many serious health risks such as cardiovascular disease, obesity, and nonalcoholic fatty liver disease. Maternal high-fat diet (MHFD) can alter offspring metabolism and predispose offspring to obesity through many mechanisms, including alterations in immune cell function. However, whether maternal diet impacts development of the neonatal immune system remains unclear. To investigate the impact of MHFD on offspring bone marrow, a major site of immune cell generation via hematopoiesis, we utilized two distinct cohorts of non-human primates (NHPs). Bone marrow from a cohort of early third trimester fetuses was examined to determine the effects of MHFD vs. chow diet on bone marrow cellularity and function. The second cohort, 3-year-old juvenile NHPs exposed to MHFD early in life, then shifted to a chow diet at weaning for the remaining 2.5 years, were studied to see whether bone marrow phenotypes resulting from MHFD exposure were reversible upon altering diet later in life. Colony-forming assays of plated fetal bone marrow cells showed a significant 34.5% relative increase in innate immune system cells at the expense of erythroid (-78.9%) and multilineage (-53.8%) progenitors, and a decrease in total numbers of all cell types. Bone marrow stem cells differentiated to macrophages were treated with LPS and showed significantly lower IL1B expression and trending decreased IL10 and TNF via qPCR, suggesting hyporesponsivity to inflammatory LPS stimuli. Similar phenotypes were found in the cohort of juveniles exposed to MHFD then shifted onto a chow diet, suggesting that exposure to MHFD has long lasting immunological consequences in offspring not correctable by dietary changes later in life. Further, our results suggest remodeling in macrophage function, potentially implicating an epigenetic programming event early in life driven by maternal diet. Disclosure M.J. Nash: None. T.K. Soderborg: None. R.C. Janssen: None. E.M. Pietras: None. J.E. Friedman: Advisory Panel; Self; Janssen Pharmaceuticals, Inc..