Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity.

Abstract

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.

• Authors: Işın Çakır, Colleen K Hadley, Pauline Lining Pan, Rushita A Bagchi, Masoud Ghamari-Langroudi, Danielle T Porter, Qiuyu Wang, Michael J Litt, Somnath Jana, Susan Hagen, Pil Lee, Andrew White, Jiandie D Lin, Timothy A McKinsey, Roger D Cone
• Journal: Nature metabolism (Nat Metab) Vol. 4 Issue 1 Pg. 44-59 (01 2022) ISSN: 2522-5812 [Electronic] Germany
• PMID: 35039672 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

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

Topics

• Adipose Tissue (drug effects, metabolism)
• Animals
• Body Weight
• Diet, High-Fat
• Dose-Response Relationship, Drug
• Energy Metabolism (drug effects)
• Enzyme Activation
• Gene Expression Regulation (drug effects)
• Histone Deacetylase 6 (antagonists & inhibitors, genetics, metabolism)
• Histone Deacetylase Inhibitors (chemistry, pharmacology)
• Leptin (metabolism)
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Obese
• Models, Biological
• Obesity (drug therapy, etiology, metabolism)
• Signal Transduction (drug effects)