Daily Endocrinology Research Analysis

Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt - but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.

Oocyte vitrification is indispensable in assisted reproduction, yet its link to compromised embryonic development remains mechanistically unresolved. Here, this study demonstrate through integrated transcriptome and translatome analysis that vitrification disrupts maternal mRNA translation-sparing global transcriptional output-in mouse oocytes. This translational perturbation prominently suppresses genes encoding spliceosome components, including Phf5a, leading to persistent and widespread alternative splicing defects in subsequent 2-cell embryos. Importantly, aberrant splicing specifically depletes the functional full-length transcript of the essential zygotic genome activation (ZGA) regulator Crxos (Egam1) while elevating a truncated, non-functional variant (Egam1ΔEXON3). Functional analyses confirm that loss of Crxos in 2‑cell embryos not only compromises developmental progression but also reduces global transcriptional activity, likely via impaired RNA Pol II recruitment and elongation at ZGA genes. Together, this work delineates a linear pathological cascade triggered by oocyte vitrification, comprising maternal translational suppression, spliceosome impairment, Crxos aberrant splicing, impaired ZGA, and developmental compromise, thereby offering a mechanistic basis for refining cryopreservation protocols in reproductive medicine.

Several neuronal populations in the hypothalamus and brainstem express thyrotropin-releasing hormone (TRH). While TRH neurons in the paraventricular nucleus (PVN) regulate the thyroid axis, the roles of other TRH-producing neurons remain largely unknown. Here we investigate the role of TRH neurons in the PVN, the dorsomedial hypothalamus (DMH), the medial preoptic area (MPA), and the rostral raphe pallidus (RPa) for metabolism in mice. Selective activation of these populations using chemogenetics in mice revealed that TRH neurons of the hypothalamus increase food intake and influence energy homeostasis in different ways. Specifically, TRH neurons in the PVN and DMH enhance brown adipose tissue activity via a polysynaptic circuit, while MPA-located neurons increase locomotor activity and maintain cold tolerance. These effects were independent of the thyroid axis, demonstrating that TRH neurons have distinct, subtype-specific ways to increase energy expenditure beyond regulating the thyroid axis in mice.