TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons

• Published in: The Journal of clinical investigation Vol. 132; no. 19; pp. 1 - 16
• Main Authors: Xie, Di, Stutz, Bernardo, Li, Feng, Chen, Fan, Lv, Haining, Sestan-Pesa, Matija, Catarino, Jonatas, Gu, Jianlei, Zhao, Hongyu, Stoddard, Christopher E., Carmichael, Gordon G., Shanabrough, Marya, Taylor, Hugh S., Liu, Zhong-Wu, Gao, Xiao-Bing, Horvath, Tamas L., Huang, Yingqun
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.10.2022
• Subjects: Ablation; Analysis; Animal models; Appetite; Bioenergetics; Biomedical research; Cell culture; Chromatin; CRISPR; Demethylation; Diabetes; Diabetes mellitus; Drinking water; Energy; Energy expenditure; Energy metabolism; Epigenetics; Feeding behavior; Food intake; Gene expression; Gene regulation; Health aspects; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Metabolism; Neurons; Neuropeptide Y; Neuropeptides; Neuroscience; Obesity; Peptides; Proteins; Rodents; Stress (Physiology); Stress response; γ-Aminobutyric acid; United States
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI162365

The TET family of dioxygenases promote DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Hypothalamic agouti-related peptide-expressing (AGRP-expressing) neurons play an essential role in driving feeding, while also modulating nonfeeding behaviors. Besides AGRP, these neurons produce neuropeptide Y (NPY) and the neurotransmitter GABA, which act in concert to stimulate food intake and decrease energy expenditure. Notably, AGRP, NPY, and GABA can also elicit anxiolytic effects. Here, we report that in adult mouse AGRP neurons, CRISPR-mediated genetic ablation of Tet3, not previously known to be involved in central control of appetite and metabolism, induced hyperphagia, obesity, and diabetes, in addition to a reduction of stress-like behaviors. TET3 deficiency activated AGRP neurons, simultaneously upregulated the expression of Agrp, Npy, and the vesicular GABA transporter Slc32a1, and impeded leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induced 5hmC modification that was associated with a chromatin-modifying complex leading to transcription inhibition, and this regulation occurred in both the mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism and revealed its unexpected dual role in the control of feeding and other complex behaviors through AGRP neurons.