<b>FUNCTIONAL CHARACTERIZATION OF PROTEIN ARGININE METHYLTRANSFERASE 5 IN ADIPOCYTES</b>

<p dir="ltr">Adipose tissue is critical for maintaining energy homeostasis. Its dysfunction causes metabolic disorders like diabetes and obesity. Adipose tissue includes white adipose tissue (WAT), which stores and releases energy, and brown adipose tissue (BAT), responsible for dissipating energy through thermogenesis, particularly during cold exposure. The importance of protein arginine methyltransferase 5 (PRMT5) in adipose tissue has been demonstrated, yet the molecular mechanisms by which PRMT5 regulates adipocyte metabolism and its specific role in thermogenic adipocytes remain poorly understood.</p><p dir="ltr">In this work, I demonstrate that PRMT5 exhibits dynamic subcellular localization in brown adipocytes (BAs), shuttling between the nucleus, cytoplasm, and mitochondria during differentiation and cold stimulation. This mitochondrial translocation of PRMT5 is mediated by its acetylation via acetyl-CoA acetyltransferase (ACAT1). Within the mitochondria, PRMT5 methylates and stabilizes NADH:Ubiquinone Oxidoreductase Core Subunit S2 (NDUFS2). This methylation is essential for mitochondrial Complex I (C-I) assembly and function. Brown adipocyte-specific <i>Prmt5</i> knockout (<i>Prmt5</i>^UKO) mice exhibit cold intolerance, disrupted C-I assembly, impaired mitochondrial respiration, and reduced BAT mass. This study establishes a novel physiological role of PRMT5 in mitochondrial maintenance and thermogenesis.</p><p dir="ltr">Beyond mitochondrial regulation, PRMT5 also controls BAT-mediated systemic metabolism and inter-tissue communication. Under cold stress, <i>Prmt5</i>^UKO mice exhibit increased WAT lipolysis, and elevated circulating glucose levels. Under diet-induced obesity (DIO), <i>Prmt5</i>^UKO mice exhibit hepatic steatosis and insulin resistance. Mechanistically, PRMT5 suppresses interleukin-6 (IL-6) expression through H4R3me2s histone methylation at the <i>Il6</i> locus. Loss of PRMT5 leads to elevated IL-6 secretion from BAT, which mediates endocrine crosstalk with WAT, contributing to systemic metabolic dysregulation.</p><p dir="ltr">Finally, transcriptomic and lipidomic analysis reveal a broad metabolic reprogramming in <i>Prmt5</i>-deficient WAT. Adipocyte-specific <i>Prmt5 </i>knockout (<i>Prmt5</i>^AKO) mice exhibit enhanced glucose utilization, reduced lipid metabolic genes expression, altered glycerophospholipid composition, and upregulated cholesterol biosynthesis compared to controls. These changes are accompanied by hyperlipidemia, hepatic lipid accumulation, and disruption of membrane transport networks, and suggest the essential role of PRMT5 in adipocyte metabolism and lipid homeostasis.</p><p dir="ltr">Together, this study defines PRMT5 as a multi-compartmental and multi-functional regulator of adipocyte biology. PRMT5 regulates mitochondrial respiration and epigenetic control of endocrine signaling in BAT and reprograms lipid and glucose metabolism in WAT. These findings suggest PRMT5 as a promising target for therapies combating obesity and metabolic disease.</p>