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

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. How leptin signalling produces anti‑obesity effects is incompletely understood. Here, the authors demonstrate that FAK and PYK2 are required for STAT3 activation, normal leptin responses, and HDAC6 inhibitor‑mediated weight loss, with their loss causing hyperphagic obesity.