Children Exposed to Maternal Obesity or Gestational Diabetes Mellitus During Early Fetal Development Have Hypothalamic Alterations That Predict Future Weight Gain

Abstract

Objective: Exposure in utero to maternal obesity or gestational diabetes mellitus (GDM) is linked to a high risk for obesity in offspring. Animal studies suggest that these exposures disrupt the development of the hypothalamus, a brain region that regulates body weight, predisposing offspring to develop obesity. This study tested the hypothesis in humans that in utero exposure to maternal obesity and/or GDM is associated with alterations in the hypothalamic response to glucose and the altered hypothalamic response would predict greater increases in child adiposity 1 year later.

Research design and methods: Participants were 91 children aged 7-11 years with and without in utero exposure to GDM. Maternal prepregnancy BMI and GDM exposures were determined from electronic medical records. Arterial spin labeling MRI was used to determine the child's hypothalamic blood flow response to oral glucose. Anthropometric measures were acquired in all children at their initial visit and again 1 year later in a subset of 44 children.

Results: Children exposed to GDM diagnosed at ≤26 weeks' gestation had increased hypothalamic blood flow (a marker of hypothalamic activation) in response to glucose when compared with unexposed children, and results remained after adjustments for child age, sex, BMI, and maternal prepregnancy BMI. Maternal prepregnancy BMI was positively associated with the child's hypothalamic response to glucose. Greater hypothalamic response to glucose predicted greater increases in child's BMI 1 year later.

Conclusions: Increased glucose-linked hypothalamic activation during childhood represents a possible mechanism by which exposure to maternal metabolic disorders during fetal development increases future risk for obesity.

Figure 1

A: Least square (LS) mean ± SE of child hypothalamic response adjusted for child age, sex, BMI z score, and maternal prepregnancy BMI by GDM exposure categories of unexposed (gray bar), GDM diagnosed at >26 weeks’ gestation (black striped bar), and GDM diagnosed at ≤26 weeks’ gestation (black bar). B: Child age, sex, and BMI z score adjusted residuals of hypothalamic response to glucose by maternal prepregnancy BMI. Unexposed children indicated by white circles, GDM diagnosed >26 weeks (wks) by gray squares, and GDM diagnosed ≤26 weeks by black triangles. C: Representative figure showing the hypothalamic ROI in sagittal, coronal, and axial planes. X, Y, and Z refer to Montreal Neurological Institute atlas coordinates.

Figure 2

Child age, sex, and baseline BMI adjusted residuals of the change in BMI by hypothalamic response to glucose. Unexposed children indicated by white circles, GDM diagnosed >26 weeks (wks) by gray squares, and GDM diagnosed ≤26 weeks by black triangles.