eNews June 08, 2016

Exposure to increased leptin in utero influences cardiovascular phenotypes in offspring

Gestational diabetes and acquired metabolic disease

The risks for developing cardiovascular or metabolic disorders such as hypertension, diabetes, and obesity are increased in offspring whose mothers had some of these conditions during gestation, especially gestational diabetes mellitus (GDM).  Inherited genetic factors certainly influence the incidences and severities of these disorders, but accumulating evidence suggests that the maternal environment during gestation also contributes significantly to cardiovascular and metabolic phenotypes in offspring after birth.  In utero programming is hypothesized to result exposure to maternal hormones or metabolites that affect signaling pathways in the developing fetus and that subsequently influence postnatal phenotypes.  Population association studies have demonstrated that boys born to mothers with GDM have elevated systolic blood pressure.  Hypertensive phenotypes also are observed in mouse and rat offspring born to dams who were administered streptozotocin during pregnancy to deplete pancreatic beta cells and induce type I diabetes.  The actual signals that induce the increased blood pressure and vascular changes observed in the offspring of diabetic/obese mothers, however, are not known.  In a May 2016 study published online in PLoSOne, a research team lead by Dr. Laura C. Schulz at the University of Missouri examined the degree of hypertension and vascular dysfunction in offspring of hyperleptinemic female mice.  Their data demonstrates that high maternal leptin levels predispose offspring, especially males, to cardiovascular disorders later in life, especially if they consume a high fat diet.  The insights gained from the Schulz team’s study may suggest intervention or treatment strategies for mothers with GDM and other metabolic conditions that might help to protect their children from developing similar conditions as they grow.

High maternal leptin promotes cardiovascular changes in offspring

Leptin resistance and resulting hyperleptinemia is a commonly observed in women with GDM.  Leptin is a hormone that regulates satiety and, thus, energy homeostasis, and defects in leptin production or signaling lead to obesity and diabetes.  To investigate the effects of maternal hyperleptinemia on programming cardiovascular phenotypes in offspring, Dr. Schulz and her team used leptin receptor-deficient B6.BKS(D)-Leprdb/J (Stock# 000697). Leprdb homozygote females are severely glucose intolerant and frequently used to evaluate diabetes and obesity phenotypes, but they do not breed and cannot be used as models for mothers with GDM.  However, heterozygote (Leprdb/+) females, although they are not glucose intolerant or diabetic, do have very high leptin levels.  Previously, the researchers demonstrated that wild-type offspring from Leprdb/+ mothers become fatter than controls and developed glucose intolerance.  Further, they demonstrated these phenotypes were more robust in male versus female offspring.  Treatment of pregnant wild-type dams with exogenous leptin produced the same effect, suggesting that the hyperleptinemia of the Leprdb/+ mothers is a major signal that drives these postnatal phenotypes. 

To determine more specifically how maternal leptin exposure affects cardiovascular and hypertension phenotypes, Dr. Schulz’s team evaluated the structure and function of mesenteric resistance arteries in male offspring and compared them to measurements from the offspring of wild-type females. They focused on resistance arteries because these structures play a large role in regulating blood pressure, and changes in them are associated with vascular disorders and hypertension.  Data were collected from offspring at young (6 weeks) and adult (31 weeks) ages that had been maintained on a standard diet and from 31 week-old adults after feeding them with a high fat diet for 6 weeks.  Blood pressure was not elevelated in either the young or old offspring from hyperleptinemic mothers compared with same-aged offspring from wild-type mothers. In contrast, high fat diet feeding increased blood pressure readings in adult offspring from both hyperleptinemic and wild-type females, but no difference between the two groups was observed. 

When young, pups from hyperleptinemic and wild-type dams responded similarly to compounds that stimulate either vasoconstriction or vasodilation.  In adults, however, differences emerged that also were diet-dependent. For example, in the high fat diet-fed offspring from Leprdb/+ females, mesenteric artery vasodilation in response to insulin was significantly blunted when compared to the responses in either high fat diet-fed wild-type-derived pups or Leprdb/+-derived pups maintained on the standard diet.   These observations suggest that contributions from both the maternal environment and diet on vasculature responses were supported by data evaluating the mechanical and structural characteristics of the vessels, too.  Arteries from the high fat diet-fed adult offspring from Leprdb/+ mothers were more stiff, less elastic, and had reduced F-actin and elastin components than arteries from mice on a standard diet.  Lastly, the number of fenestrae in these vessels, which allow for flexibility and aid in vasodilatory responses was the same in adult offspring from Leprdb/+ mothers and wild-type mothers, but were reduced in offspring from Leprdb/+ mothers fed a high fat diet.   Altogether, these data suggest that programming in utero in hyperleptinemic mothers can predispose offspring to develop cardiovascular phenotypes postnatally following high fat diet feeding. 

This data provides new insight into the link between diet-related cardiovascular disorders and maternal programming during gestation.  Although inherited genetic factors play a significant role in determining an individual’s predisposition to developing hypertension and other cardiovascular disorders, a thorough understanding of the factors that can modify that risk, such as leptin exposure in utero, may lead to new treatment and prevention paradigms that might help to reduce the incidences for cardiovascular disease in children born from GDM mothers.