Background: Maternal obesity has become more prevalent over the last few decades, and it has been associated with negative impacts on the health of offspring.¹ The estimated prevalence of overweight or obesity status in pregnancy in the United States is 55%-63%, and it is estimated that 39 million pregnancies per year are complicated by maternal obesity, globally.^2,3 Overnutrition during critical periods of fetal development may predispose newborns to obesity in adulthood.¹ There are studies that have demonstrated that the neurogenesis of the fetal hypothalamus, insulin resistance, and feeding pathways are altered by maternal obesity.² In this review, the mechanisms in how maternal obesity can alter fetal hypothalamic development, inflect ER stress in the fetus, alter the blood-brain barrier, and induce epigenetic changes in the Pomc gene are analyzed. These findings can serve to promote wellness and healthier eating to enhance the quality of life of future generations.

Objective: This study will explore the mechanisms by which maternal obesity impacts the development of the fetal hypothalamus and contributes to metabolic disorders later in life.

Search Methods: An online search in the PubMed database was conducted from 2018-2024 using the search terms: “fetal brain development”, “maternal obesity”, “epigenetic modifications”, and “nutrition”.

Results: Throughout multiple studies, it was found that offspring exposed to maternal obesity were at risk for being overweight or developing Type II diabetes. In a mouse model, it was shown that the fetal hypothalamic neural progenitor cells were reduced, fetal hypothalamic insulin resistance increased, and Notch signaling pathways were altered.⁴ In another study, it was discovered that endoplasmic reticulum stress was induced in important metabolic tissues such as the hypothalamus in the fetus by maternal obesity.⁵ ER stress contributes to the interruption of arcuate axon growth and may affect how the hypothalamus detects fatty acids to monitor energy balance.⁵ It was discovered that mothers who consumed a high fat diet altered the function of the BBB at the median eminence-arcuate nucleus of the fetus. The integrity of the BBB was restored by breastfeeding.⁶ To determine if there is a long-term impact on the offspring’s Pomc gene due to maternal obesity, a mouse model was used. The Pomc gene in the hypothalamus suppresses food intake and was hypermethylated in the enhancer and promoter region of the fetus due to maternal obesity.⁷ These modifications prevent a response to leptin upon stimulation of Pomc gene expression and affect energy homeostasis.⁷ Long term epigenetic changes predispose the offspring to metabolic diseases. Offspring born to obese mothers were more at risk to consuming a high fat diet and developed insulin resistance.⁷

Conclusion: Research models have shown that maternal obesity predisposes offspring to metabolic disorders such as obesity and Type 2 diabetes later in life. Overnutrition during pregnancy can lead to alterations of fetal hypothalamic development, leptin sensitivity, BBB integrity, and the Pomc gene. Future studies could lead to effective therapeutic options to reduce epigenetic transmission of obesity.

Works Cited:

1. Şanlı E, Kabaran S. Maternal Obesity, Maternal Overnutrition and Fetal Programming: Effects of Epigenetic Mechanisms on the Development of Metabolic Disorders. Curr Genomics. 2019;20(6):419-427. doi:10.2174/1389202920666191030092225
2. Langley-Evans SC, Pearce J, Ellis S. Overweight, obesity and excessive weight gain in pregnancy as risk factors for adverse pregnancy outcomes: A narrative review. J Hum Nutr Diet. 2022;35(2):250-264. doi:10.1111/jhn.12999
3. Poon K. Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus. Front Endocrinol (Lausanne). 2020;11:591559. Published 2020 Nov 26. doi:10.3389/fendo.2020.591559
4. Dearden L, Buller S, Furigo IC, Fernandez-Twinn DS, Ozanne SE. Maternal obesity causes fetal hypothalamic insulin resistance and disrupts development of hypothalamic feeding pathways. Mol Metab. 2020 Dec;42:101079. doi: 10.1016/j.molmet.2020.101079. Epub 2020 Sep 9. PMID: 32919096; PMCID: PMC7549144
5. Park S, Jang A, Bouret SG. Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic development in the offspring. PLoS Biol. 2020;18(3):e3000296. Published 2020 Mar 12. doi:10.1371/journal.pbio.3000296
6. Haddad-Tóvolli R, Morari J, Barbizan R, et al. Maternal obesity damages the median eminence blood-brain barrier structure and function in the progeny: the beneficial impact of cross-fostering by lean mothers. Am J Physiol Endocrinol Metab.
7. Gali Ramamoorthy T, Allen TJ, Davies A, et al. Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats. Int J Obes (Lond). 2018;42(8):1431-1444. doi:10.1038/s41366-018-0094-1