TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons
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, thes...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI162365 |
| _version_ | 1797634505005072384 |
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| author | Di Xie Bernardo Stutz Feng Li Fan Chen Haining Lv Matija Sestan-Pesa Jonatas Catarino Jianlei Gu Hongyu Zhao Christopher E. Stoddard Gordon G. Carmichael Marya Shanabrough Hugh S. Taylor Zhong-Wu Liu Xiao-Bing Gao Tamas L. Horvath Yingqun Huang |
| author_facet | Di Xie Bernardo Stutz Feng Li Fan Chen Haining Lv Matija Sestan-Pesa Jonatas Catarino Jianlei Gu Hongyu Zhao Christopher E. Stoddard Gordon G. Carmichael Marya Shanabrough Hugh S. Taylor Zhong-Wu Liu Xiao-Bing Gao Tamas L. Horvath Yingqun Huang |
| author_sort | Di Xie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:44Z |
| format | Article |
| id | doaj.art-6327ef9376aa4b878e87ef53442e9d52 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:44Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-6327ef9376aa4b878e87ef53442e9d522023-11-07T16:19:23ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-10-0113219TET3 epigenetically controls feeding and stress response behaviors via AGRP neuronsDi XieBernardo StutzFeng LiFan ChenHaining LvMatija Sestan-PesaJonatas CatarinoJianlei GuHongyu ZhaoChristopher E. StoddardGordon G. CarmichaelMarya ShanabroughHugh S. TaylorZhong-Wu LiuXiao-Bing GaoTamas L. HorvathYingqun HuangThe 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.https://doi.org/10.1172/JCI162365MetabolismNeuroscience |
| spellingShingle | Di Xie Bernardo Stutz Feng Li Fan Chen Haining Lv Matija Sestan-Pesa Jonatas Catarino Jianlei Gu Hongyu Zhao Christopher E. Stoddard Gordon G. Carmichael Marya Shanabrough Hugh S. Taylor Zhong-Wu Liu Xiao-Bing Gao Tamas L. Horvath Yingqun Huang TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons The Journal of Clinical Investigation Metabolism Neuroscience |
| title | TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons |
| title_full | TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons |
| title_fullStr | TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons |
| title_full_unstemmed | TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons |
| title_short | TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons |
| title_sort | tet3 epigenetically controls feeding and stress response behaviors via agrp neurons |
| topic | Metabolism Neuroscience |
| url | https://doi.org/10.1172/JCI162365 |
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