| Fat mass and obesity‑associated protein (FTO) is a member of the Fe²⁺‑ and 2‑oxoglutarate‑dependent dioxygenase family and functions primarily as an RNA N6‑methyladenosine (m6A) and DNA demethylase that fine‑tunes post‑transcriptional and transcriptional programs linked to energy homeostasis and obesity‑associated traits. FTO contains a conserved catalytic double‑stranded β‑helix domain that coordinates iron and 2‑oxoglutarate, allowing it to oxidatively demethylate m6A sites in select mRNA transcripts and 3‑methylthymine in DNA, with its activity modulated by N‑ and C‑terminal regulatory regions that influence subcellular localization and stability. FTO demethylates m6A residues in transcripts involved in dopaminergic signaling, feeding behavior, and energy‑balance regulation, and this erasure generally promotes mRNA stability and translation of key regulators of appetite, reward, and metabolic rate, thereby linking FTO‑dependent methylation dynamics to caloric intake and energy expenditure. FTO deficiency causes postnatal growth retardation, pronounced leanness, and elevated energy expenditure driven by systemic activation of sympathetic neurons, whereas tissue‑specific or systemic overexpression of FTO increases food intake and adiposity and predisposes to obesity, phenotypes that parallel human genetic studies showing that common FTO intronic SNPs associated with higher body mass index correlate with increased food intake and reduced activity. FTO frequently shows altered expression and acts as an oncogenic driver or tumor‑suppressor‑like node depending on cellular context. |
Lane 1: SH-SY5Y, Lane 2: Hela, Lane 3: U87MG
