# Gestational High-Fat Diet Drives Premature Differentiation of Orexigenic Neurons and Reactivity of Astrocytes in the Fetal Rat Lateral Hypothalamus

## TL;DR

A high-fat diet during pregnancy changes the development of brain cells in rat fetuses, potentially increasing obesity risk.

## Contribution

First evidence showing HFD alters both neurons and astrocytes in the fetal hypothalamus.

## Key findings

- HFD increased cell proliferation and orexinergic neuron density in fetal rat LHA.
- HFD induced early astrocyte reactivity in the fetal lateral hypothalamus.
- Both neuronal and glial components are reprogrammed by HFD prenatally.

## Abstract

Background/Objectives: Gestational exposure to a high-fat diet (HFD) reprograms hypothalamic orexigenic circuits prenatally. However, whether astrocytes, critical modulators of this system, are also imprinted by HFD in the fetal brain remains unknown. We investigated the impact of HFD on the prenatal neuroglial architecture of the lateral hypothalamic area (LHA). Methods: Female Wistar rats were fed a control or a 60% fat diet for 12 weeks. Upon reaching obesity (Lee index ≥ 310), dams were mated. Fetuses were harvested via cesarean section at term, and their brains were processed for immunohistochemistry and morphometry to assess cell proliferation, orexin neuron density, and astrocytic reactivity in the LHA. Results: HFD significantly increased cell proliferation and orexinergic neuron density, and induced early signs of astrocyte reactivity in the fetal LHA. These findings reveal that both neuronal and glial components of the LHA orexigenic axis are structurally reprogrammed before birth. Conclusions: This study provides the first evidence that HFD simultaneously alters neuronal and glial developmental trajectories in the fetal hypothalamus. The concurrent programming of astrocytes and orexigenic neurons suggests a prenatal origin for neuroinflammatory susceptibility, reframing obesity as a neurodevelopmental disorder shaped by early life nutritional environments.