Role of adipose mRNA modifications in metabolic disease

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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 reprogramming paradigm in obesity and metabolic disease.