POMC neuron METTL14/m⁶A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism.

Abstract

METTL14 mediates N6-methyladenosine (m⁶A) RNA modification, while YTHDC1 and YTHDF2 specifically bind m⁶A-methylated RNA to regulate RNA fate. POMC neurons constitute the core of the central melanocortin circuit, and POMC deficiency causes obesity in both mice and humans. However, how m⁶A-based epitranscriptomics regulates melanocortin circuit function remains unclear. Here, we generated and characterized POMC neuron-specific knockout mice lacking Mettl14 (Mettl14^ΔPOMC), Ythdc1 (Ythdc1^ΔPOMC), or Ythdf2 (Ythdf2 ^ΔPOMC). Mettl14^ΔPOMC and Ythdc1^ΔPOMC mice develop hyperphagia, obesity, glucose intolerance, insulin resistance, and hepatic steatosis in both sexes under standard chow conditions, accompanied by POMC downregulation. Conversely, POMC neuron-specific overexpression of METTL14 or YTHDC1 protects against diet-induced obesity. In contrast, Ythdf2 ^ΔPOMC mice are resistant to obesity, revealing an m⁶A-dependent balance between YTHDC1 and YTHDF2. Mechanistically, the METTL14/YTHDC1 pathway is indispensable for embryonic POMC neurogenesis, while in adults YTHDC1 maintains melanocortin circuit integrity/function. METTL14 and YTHDC1 directly target POMC and ISL1 transcripts to regulate protein expression. POMC neuron-specific restoration of POMC reverses obesity and metabolic phenotypes in Mettl14^ΔPOMC and Ythdc1^ΔPOMC mice, defining an anti-obesity METTL14/m⁶A/YTHDC1/POMC axis. These findings identify METTL14 as the m⁶A writer for POMC/ISL1 and YTHDC1 and YTHDF2 as their readers, uncovering a critical role of m⁶A epitranscriptomic regulation in melanocortin circuit development and maintenance.