2. Academic Validation
  3. The focal adhesion kinases regulate leptin action and the weight reducing effect of HDAC6 inhibition

The focal adhesion kinases regulate leptin action and the weight reducing effect of HDAC6 inhibition

  • Nat Commun. 2026 Feb 5;17(1):1212. doi: 10.1038/s41467-026-69008-9.
Colleen K Hadley # 1 2 3,  Luca Galgano # 1 4 5 6,  Yijun Gui # 1 7,  Antonio M Carvalho da Silva # 1,  Danielle T Porter 1,  Yanan Wu 1 7,  Yuanting Lai 6 8,  Mauro Torti 4,  Işın Çakır 9 10
Affiliations

Affiliations

  • 1 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 2 College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USA.
  • 3 Weill Cornell/Rockefeller/Sloan Kettering Tri-institutional MD-PhD Program, New York, NY, USA.
  • 4 Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
  • 5 Scuola Universitaria Superiore, IUSS, Pavia, Italy.
  • 6 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
  • 8 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
  • 9 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 10 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • # Contributed equally.
PMID: 41644943 DOI: 10.1038/s41467-026-69008-9
Abstract

The adipokine Leptin is a central regulator of energy metabolism. We previously showed that HDAC6 inhibitors enhance central Leptin sensitivity. Using integrative analyses of leptin-responsive hypothalamic gene expression signatures, we identified focal adhesion kinases (FAK and Pyk2) as essential for the anorectic effect of Leptin and the anti-obesity action of HDAC6 inhibitors in male mice. The effect of tubastatin A, an HDAC6 Inhibitor, is compromised in Pyk2 knockout mice, and central inhibition of focal adhesion kinases blocks tubastatin-induced weight loss. Focal adhesion kinases phosphorylate and activate the transcription factor STAT3 downstream of Leptin receptor, and Leptin signaling is attenuated when these kinases are knocked down or inhibited. Finally, hypothalamic knockdown of focal adhesion kinases blunts Leptin action, leads to hyperphagic obesity, and attenuates the anti-obesity effect of HDAC6 inhibitors. These findings suggest that FAK and Pyk2 are previously uncharacterized members of the Leptin receptor signaling and critical mediators of central Leptin sensitization.

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