Abstract
Maternal immunization with oxidized lipoproteins prior to pregnancy protects against atherogenic in utero programming by gestational hypercholesterolemia and enhances beneficial lymphocyte-dependent immune responses in offspring. To determine whether in utero programming and immunomodulation also affect insulin resistance (IR) and type 2 diabetes, we investigated the effects of immunization on glucose and insulin responses in LDL receptor-deficient mice fed regular or 60% sucrose diets, as well as in offspring fed 0.5% cholesterol or 60% sucrose diets. IR was assessed by fasting glucose and insulin levels, oral glucose tolerance tests, glucose clamps, pancreatic immunohistochemistry and plasma free fatty acid concentrations. Immunizations improved glucose responses in both genders and protected both immunized mice and their offspring against IR and type 2 diabetes. Protection occurred even under euglycemic conditions, but was greatest in obese males exposed to very obesogenic/diabetogenic conditions. Hyperinsulinemic euglycemic clamps confirmed that maternal immunization protected mainly by reducing IR, but pancreatic immunocytochemistry also indicated some protection against beta cell damage. Maternal immunization was associated with marked regulation in offspring of 4 genes relevant to diabetes and 19 genes of importance for oxidative stress, as well as increased hepatic activities of key antioxidant enzymes. These findings establish that targeted immunomodulation may be used to protect immunized subjects and their offspring against IR and type 2 diabetes, and thus to reduce cardiovascular risk. They also support the notion that in utero programming influences offspring disease not by a single mechanism, but by multiple systemic effects.
Highlights
Extensive epidemiological evidence links the in utero environment with atherosclerosis and diabetes later in life
We provide evidence that maternal immunomodulation affects in utero programming of insulin resistance (IR) and that immunization with oxidized lipoproteins protects immunized murine mothers and their offspring against IR and diabetes under euglycemic, hypercholesterolemic, and hyperglycemic conditions
The 0.5% cholesterol diet enhanced the spontaneous hypercholesterolemia of LDLR-/mice, but the 60% sucrose diet was more obesogenic and affected lipoprotein profiles and oral glucose tolerance tests (OGTTs) glucose responses to a greater extent, especially in males (A–D)
Summary
Extensive epidemiological evidence links the in utero environment with atherosclerosis and diabetes later in life. The increasing prevalence of maternal obesity and related dysmetabolic conditions is expected to lead to a wave of cardiovascular disease in their children, but little is known about the mechanisms of pathogenic in utero programming and its prevention. Studies on one such maternal dysmetabolic condition, hypercholesterolemia, have shown that interventions in mothers may provide life-long benefits to offspring [1,2]. Even if only temporary, is associated with increased fatty streak formation in human fetal arteries and accelerated atherogenesis during normocholesterolemic childhood [3,4,5]. An influence of genetic differences could not be ruled out in humans, conclusive evidence for atherogenic programming by maternal hypercholesterolemia was obtained in animal models [1,6,7]. The recent observation that offspring with heterogeneous familial hypercholesterolemia (FH) who inherited FH from their mother and were exposed to higher maternal cholesterol levels in utero had greater overall mortality than those who inherited FH from their father supports the pathogenic role of maternal hypercholesterolemia [8]
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