Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss

Cell Metab. 2024 Apr 2;36(4):857-876.e10. doi: 10.1016/j.cmet.2024.02.007.

Abstract

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.

Keywords: HDAC6 inhibitors; acetylation; anti-obesity drug; leptin receptor; leptin resistance; obesity; obesity treatment; translational medicine; type 2 diabetes.

MeSH terms

  • Animals
  • Histone Deacetylase 6
  • Leptin* / metabolism
  • Mice
  • Obesity* / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism
  • Weight Gain
  • Weight Loss

Substances

  • Histone Deacetylase 6
  • Leptin
  • Receptors, Leptin
  • Hdac6 protein, mouse