Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index

Mackay, Harry A.; Gunasekara, T.D.C.P.; Yam, Kit-Yi; Srisai, Dollada; Yalamanchili, Hari Krishna; Li, Yumei; Chen, Rui; Coarfa, Cristian; Waterland, Robert A.

doi:10.1126/sciadv.abo3991

Cited by 9 publications

(7 citation statements)

References 98 publications

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“…We observed sex-specific POMC methylation, supporting a previous finding in mouse hypothalamic arcuate nucleus and disease-related epigenome-wide association studies, for example, for Alzheimer’s disease ( 44 – 46 ). The molecular cause for this sexual dimorphism remains elusive and needs to be addressed in future studies.…”

Section: Discussionsupporting

confidence: 90%

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment

et al. 2023

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Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC -expressing neurons. On the basis of these findings, we treated POMC -hypermethylated obese individuals ( n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.

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Section: Discussionsupporting

confidence: 90%

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment

et al. 2023

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“…Recently, MacKay et al . showed a differential methylation pattern of specific genes expressed in neurons of the ARH across postnatal development (P12-P35), including Glp1r and Cck in male mice, and Gipr and Cck in females, strengthening the role of these gut peptides on the hypothalamic development in a sex-specific manner [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus

Cantacorps,

Coull,

Falck

et al. 2023

PLoS ONE

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Objective In adult organisms, a number of receptors have been identified which modulate metabolic processes related to peptides derived from the intestinal tract. These receptors play significant roles in glucose homeostasis, food intake and energy balance. Here we assess these classical metabolic receptors and their expression as well as their potential role in early development of hypothalamic neuronal circuits. Methods Chow-fed C57BL6/N female mice were mated and hypothalamic tissue was collected from offspring across postnatal development (postnatal day 7–21). Subsequent qPCR and Western Blot analyses were used to determine mRNA and protein changes in gut-derived peptide hormone receptors. Correlations to body weight, blood glucose and circulating leptin levels were analyzed. Results We describe the gene expression and dynamic protein regulation of key gut-derived peptide hormone receptors in the early postnatal period of the mouse brain. Specifically, we show changes to Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide 1 receptor (GLP1R), and cholecystokinin receptor 2 (CCK2R) in the developing hypothalamus. The changes to GIPR and InsR seem to be strongly negatively correlated with body weight. Conclusions This comprehensive analysis underscores the need to understand the roles of maternal-derived circulating gut hormones and their direct effect on offspring brain development.

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“…The activity of both methylating and demethylating enzymes in the hypothalamus is developmentally regulated and shows different activity patterns between male and female brains (29). Most recently, MacKay et al have shown that post-natal epigenetic maturation in the ARC is cell type and sex specific and occurs particularly in genomic regions enriched for heritability of BMI in humans (30).…”

Section: Epigenetic Regulation Of Neural Maturationmentioning

confidence: 99%

“…Most recently, MacKay et al. have shown that post-natal epigenetic maturation in the ARC is cell type and sex specific and occurs particularly in genomic regions enriched for heritability of BMI in humans ( 30 ).…”

Section: Development Of Hypothalamic Energy Balance Circuitsmentioning

confidence: 99%

Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function

Furigo

Dearden

2022

Front. Endocrinol.

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As obesity rates have risen around the world, so to have pregnancies complicated by maternal obesity. Obesity during pregnancy is not only associated with negative health outcomes for the mother and the baby during pregnancy and birth, there is also strong evidence that exposure to maternal obesity causes an increased risk to develop obesity, diabetes and cardiovascular disease later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is usually preceded by increased food intake, implicating altered neuronal control of food intake as a likely area of change. The hypothalamus is the primary site in the brain for maintaining energy homeostasis, which it coordinates by sensing whole body nutrient status and appropriately adjusting parameters including food intake. The development of the hypothalamus is plastic and regulated by metabolic hormones such as leptin, ghrelin and insulin, making it vulnerable to disruption in an obese in utero environment. This review will summarise how the hypothalamus develops, how maternal obesity impacts on structure and function of the hypothalamus in the offspring, and the factors that are altered in an obese in utero environment that may mediate the permanent changes to hypothalamic function in exposed individuals.

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Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index

Cited by 9 publications

References 98 publications

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment

Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus

Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function

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