ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Obesity
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1680158
This article is part of the Research TopicTargeting Adipose Tissue for the Treatment of Metabolic AlterationsView all 11 articles
Increased spontaneous physical activity of female MEST-deficient mice protects against dietary obesity
Provisionally accepted
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, United States
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Introduction: Mesoderm specific transcript (Mest), a paternally expressed imprinted gene, is involved in the modulation of adipose tissue expansion. Likewise, Mest is highly expressed in developing and adult brain, suggesting its involvement in behavioral phenotypes. Previously, we showed that female mice with paternal Mest inactivation (MestpKO) have no discernible behavioral impairments compared to wild type. In this study, we performed metabolic phenotyping of female MestpKO mice in response to a dietary challenge. Methods: Eight-week-old female and male wild type and MestpKO mice were fed control or Western diet (40 kcal% fat) until 24 weeks of age. Body weight and composition, metabolic parameters were measured during the course of the feeding regimens and gene expression and type-2-deiodinase (DIO2) activity were examined in white adipose tissue and brain at the completion of the study. Results: MestpKO female mice fed western diet were protected against diet-induced obesity. Strikingly, these mice showed increased ambulatory activity and speed coupled with reduced resting parameters, suggesting involvement of MEST in regulation of spontaneous physical activity, a form of non-exercise activity thermogenesis. When considering body mass (control diet) and lean mass (Western diet), energy expenditure was increased in the female MestpKO mice. Male MestpKO mice did not exhibit this behavior. Analyses of hypothalamic gene expression revealed the upregulation of Dio2 and RNA-seq highlighted differential expression of a myriad of thyroid hormone responsive genes in MestpKO female mice. Conclusion: Mechanistically, our results suggest that direct or indirect regulation of thyroid hormone-responsive genes by MEST in the hypothalamus modulates the neurobiological control of non-exercise activity thermogenesis in Western diet-fed female mice.
Keywords: Obesity, Adipose Tissue, Hypothalamus, epigenetics, mouse models, physical activity, Thyroid Hormones
Received: 05 Aug 2025; Accepted: 15 Oct 2025.
Copyright: © 2025 Koza, Anunciado-Koza, Martinez, DeMambro and Hernandez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Robert Koza, robert.koza@mainehealth.org
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