The Effects of Maternal Obesity on the Innate Immune System

Abstract

The global epidemic of obesity has led to an increasing number of obese women in childbearing age. It is now understood that maternal obesity has harmful consequences on fetal and adult health. The underlying mechanism of metabolic programming via maternal obesity remains elusive. Macrophages are important metabolite-sensing cells and mediators of pathological conditions caused by overnutrition. Interestingly, most tissue-resident macrophages have a fetal origin, which places these cells in a unique position of sensing and responding to metaflammation during embryogenesis. Kupffer cells (KCs) are the tissue-resident macrophages of the liver, therefore key candidates for metabolic programming.<br /> Here, a mouse model was used to show how maternal obesity induces metabolic programming of KCs. Non-alcoholic or metabolic steatohepatitis (NASH) develops in offspring liver upon maternal obesity if the offspring follows a healthy control diet. Myeloid cell dynamics are investigated via a flow cytometric approach, and transcriptional analysis reveals immunometabolic modulation of KCs. A metabolic shift of KCs was observed from oxidative phosphorylation to glycolysis. Genetic manipulation of macrophages targeting HIF-1α rescued maternal obese offspring from NASH. Ligand-receptor interactions were targeted between KCs and hepatocytes, comparing rescued versus NASH samples. Moreover, the multi-omics approach of hepatocyte transcriptome and liver lipidome shed light on apolipoproteins, cholesterol esters (CE), and triacylglycerols (TAG) as the causative chain of maternal obesity-induced developmental programming leading to NASH.<br /> Thus, we conclude that maternal obesity induces developmental programming of KCs. It leads to a high accumulation of TAG and CE in the liver and overexpression of Apolipoproteins in KCs. Therefore, NASH is developed, and a pathological amount of cholesterol may be carried to the bloodstream, inducing a whole-body metabolic assessment. Developmental programming may lead to further chronic diseases, and KCs are causative to those pathological mechanisms further in the individual's life.