Other
10 Authors
- Hernández MAS,
- Li HS,
- Bartlett A,
- Ozcan U,
- Guan D,
- Men Y,
- Mazitschek R,
- Yi X,
- Xu J,
- Kong D
| First Author | Guan D | Year | 2024 |
| Journal | Cell Metab | Volume | 36 |
| Issue | 4 | Pages | 857-876.e10 |
| PubMed ID | 38569472 | Mgi Jnum | J:347397 |
| Mgi Id | MGI:7623033 | Doi | 10.1016/j.cmet.2024.02.007 |
| Citation | Guan D, et al. (2024) Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss. Cell Metab 36(4):857-876.e10 |
| abstractText | Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents. |
