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Fetal Programming of the Human Hypothalamus: A Role for Maternal Nutrition During Pregnancy

Thu, March 23, 3:15 to 4:45pm, Salt Palace Convention Center, Floor: 1, Meeting Room 151 G

Abstract

Introduction: Preclinical studies suggest that maternal obesity/overnutrition during pregnancy elicits structural changes to the developing offspring hypothalamus (HTH) that are, in turn, of functional consequence to offspring obesity-risk. Yet, despite the well-established importance of the HTH in the context of energy (im)balance and obesity-risk, the developing HTH circuitry and its determinants of variation are poorly understood in the human context. Here, we will present data from three complimentary longitudinal prospective studies that address this knowledge gap. First (Study 1), in a large international (California and Finland) sample we test the hypothesis that maternal pre-pregnancy BMI is prospectively associated with MRI-based measures of newborn offspring HTH microstructure (Mean Diffusivity [MD]). Second (Study 2), in a single cohort with detailed pregnancy and offspring data, we test the specific hypothesis that maternal saturated free fatty acid (sFFAs, an effector of maternal adiposity) concentration during pregnancy is associated with newborn HTH-MD, that is in turn, associated with early childhood body fat percentage (BF%). Finally (Study 3), based on the premise that the hypothalamus is highly heterogenous in structure and function, we apply a novel pipeline for the automatic segmentation of newborn HTH sub-nuclei macrostructure in the context of Study 2.

Methods:
Study 1 (Figure 1): Participants (N=231; 2 sites) were BMI-matched across cohorts (up to Class I Obesity; BMIRange=17-35), and HTH-MD was phenotyped based on diffusion-weighted MRI using standard neonatal processing pipelines. Multiple linear regression (MLR) was used for association testing.

Study 2 (Figure 1): Maternal blood samples were collected in early/mid/late pregnancy, and sFFAs quantified using LC-MS and averaged across pregnancy. Early-childhood BF% was quantified using DXA. MLR was used for association testing.

Study 3 (Figure 2): A novel registration-based pipeline was developed in a multi-site cohort (N=214; 4 sites) with structural (T1/T2-weighted) MRI data to segment HTH sub-nuclei in the Study 2 dataset. MLR was then used to test the association between maternal sFFA and newborn HTH inferior-tubular volume, consistent with Study 2 procedures.

Results:
Study 1: Maternal pre-pregnancy BMI and newborn offspring HTH-MD were linearly associated at both sites (β ̂Site,1 = 0.22, pSite,1=0.03; β ̂Site,2 = 0.17, pSite,2 = 0.01), and remained significant after adjusting for cohort-relevant sociodemographic and clinical factors.

Study 2: Maternal sFFA concentration during pregnancy was positively associated with mean newborn HTH-MD (R2=5.6%;p=0.02) and mean newborn HTH-MD was positively associated with early-childhood BF% (R2=14.7%;p=0.01). Both remained significant after adjusting for relevant sociodemographic and clinical factors.

Study 3: Automatic HTH sub-nuclei segmentations demonstrated proper agreement with expert-rated manual segmentations, and maternal sFFA concentration during pregnancy was negatively associated with mean newborn inferior-tubular volume (R2=6.2%;p=0.01) and remained significant after adjusting for cohort-relevant sociodemographic and clinical factors.

Conclusions: Collectively, this data represents some of the first observational evidence in human newborns that maternal nutritional status before/during pregnancy is prospectively associated with micro/macrostructural variation in the offspring HTH, that structural variation in the human newborn HTH is prospectively associated with early life adiposity outcomes (energy imbalance), and that phenotyping HTH structure at the sub-nuclei scale may provide added benefit to future investigations of human HTH development.

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