Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity

被引：46

作者：

Cakir, Ism ^{[1
]}

Hadley, Colleen K. ^{[1
,2
]}

Pan, Pauline Lining ^{[1
,13
]}

Bagchi, Rushita A. ^{[3
,4
]}

Ghamari-Langroudi, Masoud ^{[5
,6
]}

Porter, Danielle T. ^{[1
]}

Wang, Qiuyu ^{[1
]}

Litt, Michael J. ^{[5
,7
]}

Jana, Somnath ^{[8
]}

Hagen, Susan ^{[9
]}

Lee, Pil ^{[9
]}

White, Andrew ^{[9
,10
]}

Lin, Jiandie D. ^{[1
,11
]}

McKinsey, Timothy A. ^{[3
,4
]}

Cone, Roger D. ^{[1
,12
]}

机构：

[1] Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Coll Literature Sci & Arts, Ann Arbor, MI 48109 USA

[3] Univ Colorado, Div Cardiol, Dept Med, Anschutz Med Campus, Aurora, CO USA

[4] Univ Colorado, Consortium Fibrosis Res & Translat, Anschutz Med Campus, Aurora, CO USA

[5] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Dept Pharmacol, Warren Ctr Neurosci Drug Discovery, Nashville, TN USA

[7] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[8] Vanderbilt Inst Chem Biol, Chem Synth Core, Nashville, TN USA

[9] Univ Michigan, Coll Pharm, Nahlteich Med Chem Core, 428 Church St, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Coll Pharm, Dept Med Chem, Ann Arbor, MI 48109 USA

[11] Univ Michigan, Michigan Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

[12] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[13] Univ Michigan, Med Ctr, Dept Pharmacol, Ann Arbor, MI 48109 USA

来源：

NATURE METABOLISM | 2022年 / 4卷 / 01期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

DIET-INDUCED OBESITY; INSULIN-RESISTANCE; SKELETAL-MUSCLE; FOOD-INTAKE; GLUCOSE-HOMEOSTASIS; BODY-WEIGHT; MOUSE MODEL; HDAC6; STRESS; SIGNAL;

D O I：

10.1038/s42255-021-00515-3

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Inhibiting the cytosolic enzyme histone deacetylase 6 in the periphery is sufficient to improve leptin sensitivity and metabolic outcomes in diet-induced obese mice. 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.

引用

页码：44 / +

页数：34

共 87 条

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