Academic Journal
The focal adhesion kinases regulate leptin action and the weight reducing effect of HDAC6 inhibition.
| Τίτλος: | The focal adhesion kinases regulate leptin action and the weight reducing effect of HDAC6 inhibition. |
|---|---|
| Συγγραφείς: | Hadley CK; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.; College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USA.; Weill Cornell/Rockefeller/Sloan Kettering Tri-institutional MD-PhD Program, New York, NY, USA., Galgano L; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.; Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.; Scuola Universitaria Superiore, IUSS, Pavia, Italy.; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Gui Y; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA., Carvalho da Silva AM; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., Porter DT; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., Wu Y; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA., Lai Y; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China., Torti M; Department of Biology and Biotechnology, University of Pavia, Pavia, Italy., Çakır I; Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. cakiri@pitt.edu.; Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. cakiri@pitt.edu. |
| Πηγή: | Nature communications [Nat Commun] 2026 Feb 05; Vol. 17 (1), pp. 1212. Date of Electronic Publication: 2026 Feb 05. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| Ιατρικοί όροι (MeSH): | Leptin*/metabolism , Leptin*/pharmacology , Histone Deacetylases*/metabolism , Focal Adhesion Kinase 2*/metabolism , Focal Adhesion Kinase 2*/genetics , Histone Deacetylase Inhibitors*/pharmacology , Focal Adhesion Kinase 1*/metabolism , Focal Adhesion Kinase 1*/genetics , Weight Loss*/drug effects, Histone Deacetylase 6/antagonists & inhibitors ; Hydroxamic Acids/pharmacology ; Indoles/pharmacology ; Receptors, Leptin/metabolism ; Hypothalamus/metabolism ; Hypothalamus/drug effects ; Signal Transduction/drug effects ; STAT3 Transcription Factor/metabolism ; Obesity/metabolism ; Obesity/drug therapy ; Obesity/genetics ; Animals ; Male ; Mice ; Mice, Knockout ; Phosphorylation ; Mice, Inbred C57BL |
| Περίληψη: | 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. (© 2026. The Author(s).) |
| Competing Interests: | Competing interests: I.C. is an inventor on a provisional patent application on non-hydroxamate HDAC6 blockers. Other authors declare no competing interests. |
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| Grant Information: | P30 DK020572 United States DK NIDDK NIH HHS; R01 DK070332 United States DK NIDDK NIH HHS; R01 DK125830 United States DK NIDDK NIH HHS; T32 GM152349 United States GM NIGMS NIH HHS |
| Substance Nomenclature: | 0 (Leptin) EC 3.5.1.98 (Histone Deacetylase 6) 0 (Hydroxamic Acids) EC 3.5.1.98 (Histone Deacetylases) EC 2.7.10.2 (Focal Adhesion Kinase 2) 0 (Histone Deacetylase Inhibitors) 0 (Indoles) 0 (Receptors, Leptin) 0 (STAT3 Transcription Factor) EC 2.7.10.2 (Focal Adhesion Kinase 1) EC 3.5.1.98 (Hdac6 protein, mouse) 2XTSOX1NF8 (tubastatin A) EC 2.7.10.2 (Ptk2 protein, mouse) EC 2.7.10.2 (Ptk2b protein, mouse) |
| Entry Date(s): | Date Created: 20260205 Date Completed: 20260706 Latest Revision: 20260706 |
| Update Code: | 20260707 |
| PubMed Central ID: | PMC12877105 |
| DOI: | 10.1038/s41467-026-69008-9 |
| PMID: | 41644943 |
| Βάση Δεδομένων: | MEDLINE |
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