# Role of adipose mRNA modifications in metabolic disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $455,270

## Abstract

Abstract
Excessive white adipose tissue (WAT) is a hallmark of obesity and a causal factor for obesity-associated
disease. Adipose secretion of adipokines is also dysregulated in obesity, further impairing WAT crosstalk with
other tissues. Extensive research has been focused on gene transcriptions and protein posttranslational
modifications and substantially advanced our understanding of WAT growth and functions. Importantly, mRNA
connects the genetic control to translation of proteins responsible for cellular activities and functions. Like
protein modifications, RNA is also extensively and reversibly modified in its life cycle. N6-methyladenosine
(m6A) is the predominant RNA modification and catalyzed by a Mettl3/Mettl14 methyltransferase complex
(m6A writer). YTHD family proteins (m6A readers) bind to m6A-methylated RNAs and regulate pre-mRNA
splicing, nuclear export, decay, and/or translation of target transcripts. Global deletion of Mettl3, Mettl14, or
Ythdc1 results in embryonic/neonatal death in mice, demonstrating the essential role of the m6A system in
development and survival. However, m6A-based epitranscriptomic reprogramming has not been explored in
WAT, and there is a gap in our understanding of RNA modifications and metabolism in obesity. In the
preliminary study, we generated and characterized adipocyte-specific Mettl14 (Mettl14Δfat) and Ythdc1
(Ythdc1Δfat) knockout mice. Remarkably, both Mettl14Δfat and Ythdc1Δfat mice were resistant to diet-induced
obesity, type 2 diabetes, and liver steatosis. Gene expression analysis suggested that Mettl14 and Ythdc1
target the lipolysis machinery, β adrenergic signaling (stimulating lipolysis), insulin signaling (suppressing
lipolysis), and adipokine secretion. Consistently, WAT lipolysis was substantially elevated in Mettl14Δfat mice
and Ythdc1Δfat mice, particularly under β adrenergic-stimulated conditions, contributing to WAT reduction.
Adipose adiponectin expression was elevated in Mettl14Δfat and Ythdc1Δfat mice, contributing to improved
insulin resistance, glucose metabolism, and liver steatosis. We hypothesize that Mettl14 induces m6A
methylation selectively in mRNAs governing the lipolysis machinery, β adrenergic signaling, insulin signaling,
and adipokine expression. Ythdc1 directly binds to and regulates the metabolism (pre-mRNA splicing, nuclear
export, decay) of these m6A-modificed mRNAs, thereby guiding lipolysis, WAT growth, and adipokine-
mediated adipose crosstalk with other tissues. We will test this hypothesis in 3 Aims. Aim 1 is to determine
whether Mettl14 inhibits lipolysis and increases WAT expansion through RNA m6A methylation. Aim 2 is to
determine whether Ythdc1 suppresses lipolysis and promotes WAT expansion by regulating metabolism of its
bound RNAs. Aim 3 is to delineate whether Mettl14/Ythdc1 axis coordinates adipose crosstalk with other
tissues via adipokines. The outcomes are expected to establish a new adipose Mettl14/m6A/Ythdc1-based
epitranscriptomic reprogramm...

## Key facts

- **NIH application ID:** 10796971
- **Project number:** 5R01DK130111-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** LIANGYOU RUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,270
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796971

## Citation

> US National Institutes of Health, RePORTER application 10796971, Role of adipose mRNA modifications in metabolic disease (5R01DK130111-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10796971. Licensed CC0.

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