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Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity.
- Source :
-
Nature metabolism [Nat Metab] 2022 Jan; Vol. 4 (1), pp. 44-59. Date of Electronic Publication: 2022 Jan 17. - Publication Year :
- 2022
-
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.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Adipose Tissue drug effects
Adipose Tissue 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 genetics
Histone Deacetylase 6 metabolism
Histone Deacetylase Inhibitors chemistry
Liver drug effects
Liver metabolism
Liver pathology
Male
Mice
Mice, Obese
Models, Biological
Obesity drug therapy
Obesity etiology
Signal Transduction drug effects
Histone Deacetylase 6 antagonists & inhibitors
Histone Deacetylase Inhibitors pharmacology
Leptin metabolism
Obesity metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2522-5812
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 35039672
- Full Text :
- https://doi.org/10.1038/s42255-021-00515-3