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Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity.

Işın ÇakırColleen K HadleyPauline Lining PanRushita A BagchiMasoud Ghamari-LangroudiDanielle T PorterQiuyu WangMichael J LittSomnath JanaSusan HagenPil LeeAndrew WhiteJiandie D LinTimothy A McKinseyRoger D Cone
Published in: Nature metabolism (2022)
The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity.
Keyphrases
  • histone deacetylase
  • insulin resistance
  • adipose tissue
  • metabolic syndrome
  • weight loss
  • weight gain
  • high fat diet induced
  • type diabetes
  • high fat diet
  • skeletal muscle
  • risk assessment