POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism
Year: 2026
Type: article
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 (Mettl14ΔPOMC), Ythdc1 (Ythdc1ΔPOMC), or Ythdf2 (Ythdf2 ΔPOMC). Mettl14ΔPOMC and Ythdc1ΔPOMC 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 Mettl14ΔPOMC and Ythdc1ΔPOMC 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. POMC deficiency causes obesity in mice and humans. Here authors uncover a pivotal role of a METTL14/YTHDC1/POMC pathway, an RNA m6A modification-based mechanism, in controlling POMC neurogenesis, POMC expression, and body weight.
Source: Nature Communications
Authors: Yuan Li, Min-Hyun Kim, Decheng Ren, Liangyou Rui
Institutions: University of Michigan, Michigan Medicine, University of Chicago
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1309980231, Regulation of body weight, energy expenditure, and nutrient metabolism by YTHDC1 in POMC neural circuits, G1619971191, G1643687426, G2357171151, G2888473572, G32128458, G3390641816, G4984749004, The role of hypothalamic Slug in the regulation of leptin sensitivity, energy balance, and body weight, G6128743304, G6264697905, G6676104540, G9000159263, G9000231952, G9000301509
OpenAlex ID: W7154507253