Thyroid Hormone-Dependent Epigenetic Regulation of Melanocortin 4 Receptor Levels in Female Offspring of Obese Rats
| Autor: | Noam Meiri, Aron Weller, Asaf Marco, Tatiana Kisliouk, Tzlil Tabachnik |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Offspring Biology Epigenesis Genetic 03 medical and health sciences Eating Endocrinology Pregnancy Internal medicine medicine Animals Epigenetics Obesity Rats Wistar Promoter Regions Genetic Triiodothyronine Thyroid hormone receptor Methimazole digestive oral and skin physiology Thyroid Body Weight Maternal Nutritional Physiological Phenomena Rats Melanocortin 4 receptor 030104 developmental biology medicine.anatomical_structure Receptor Melanocortin Type 4 Female Melanocortin Hormone |
| Zdroj: | Endocrinology. 158(4) |
| ISSN: | 1945-7170 |
| Popis: | Maternal obesity is a risk factor for offspring obesity. The melanocortin 4 receptor (Mc4r) is one of the mediators of food intake and energy balance. The present study examined the epigenetic mechanisms underlying altered Mc4r levels in the hypothalamic paraventricular nucleus in the offspring of high-fat diet (HFD)-induced obese dams and sought to elucidate the role of thyroid hormones in epigenetic regulation and tagging of their nucleosome at the Mc4r promoter. Female Wistar rats were fed an HFD or standard chow from weaning through gestation and lactation. Epigenetic alterations were analyzed in the offspring on postnatal day 21 at the Mc4r promoter using chromatin immunoprecipitation and bisulfite sequencing. To study the role of triiodothyronine (T3) in Mc4r downregulation, dams received methimazole (MMI), an inhibitor of thyroid hormone production. Offspring of HFD-fed dams had a greater body weight, elevated plasma T3 concentrations, and lower Mc4r messenger RNA levels than controls. At the Mc4r promoter, offspring of HFD-fed mothers demonstrated increased histone 3 lysine 27 acetylation (H3K27ac) with a greater association to thyroid hormone receptor-β (TRβ), an inhibitor of Mc4r transcription. Moreover, TRβ coimmunoprecipitated with H3K27ac, supporting their presence in the same complex. Maternal MMI administration prevented the HFD reduction in Mc4r levels, the increase in TRβ, and the increase in the TRβ-H3K27ac association, providing further support for the role of T3 in downregulating Mc4r levels. These findings demonstrate that a perinatal HFD environment affects Mc4r regulation through a T3 metabolic pathway involving histone acetylation of its promoter. |
| Databáze: | OpenAIRE |
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