Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 19, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI162365
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Funding
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] [DK120891, DK045735, DK126447, DK119386, DK124321]
- NIH National Institute on Drug Abuse [DA046160]
- NIH National Institute of Child Health and Human Development [HD099975]
- NIH National Institute on Aging [AG067329]
- Klarman Family Foundation
- Albert McKern Memorial Fund
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The research reveals that TET3 plays a critical central role in regulating appetite and energy metabolism in adult mouse AGRP neurons, and also has an unexpected dual role in controlling other complex behaviors through 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, 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.
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