# Metabolic and xenobiotic control of thyroid hormone metabolism

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $428,667

## Abstract

ABSTRACT
 Thyroid hormones (TH) play a critical role in development. In the embryo, plasma T3 is relatively low but
TH signaling can be enhanced by expression of Dio2, the deiodinase that mediates local T3 production. The
timing of the D2-T3 activation varies among tissues, e.g. embryonic day 17 (E17) in brown adipose tissue
(BAT), or post-natal day 15 in the cochlea (P15). During the last funding period we discovered a D2-T3 peak in
the developing liver (P1-P2), coincidental with the C/EBPa-induced maturation of hepatoblasts to hepatocytes;
Dio2 expression in liver is silenced thereafter. By creating a liver-specific Dio2KO mouse (Alb-D2KO) we made
the fascinating discovery that inactivation of the D2-T3 peak modifies the liver transcriptome of the adult
mouse, with reduced expression of genes involved in lipid metabolism. The adult Alb-D2KO mouse exhibits a
dramatic phenotype of reduced susceptibility to obesity, liver steatosis and hyperlipidemia. How could a brief
perinatal peak of D2-T3 activate TH receptors (TR) and produce these changes? Hepatocytes undergo massive
postnatal epigenetic reprogramming, including changes in the DNA methylation status, some of which we now
know depend on D2-T3. We identified 1,508 CpG sites of DNA hypermethylation (H-sites) in the adult Alb-
D2KO liver genome. Thus, the perinatal D2-T3 peak ultimately affects the chromatin packing status and
transcriptional activity of adult hepatocytes, reducing the expression of 1,525 genes (RNA-seq). The proposed
studies are to identify the epigenetic mechanisms initiated by the perinatal D2-T3 peak in the liver. This is
absolutely novel and exciting as we will learn how deiodinase-mediated TH signaling affects liver development,
shaping gene expression in the adult organ.

## Key facts

- **NIH application ID:** 10810697
- **Project number:** 5R01DK077148-11
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** ANTONIO C BIANCO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $428,667
- **Award type:** 5
- **Project period:** 2007-01-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810697

## Citation

> US National Institutes of Health, RePORTER application 10810697, Metabolic and xenobiotic control of thyroid hormone metabolism (5R01DK077148-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10810697. Licensed CC0.

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