title: Imbalance between neutrophil elastase and its inhibitor α1-antitrypsin in obesity alters insulin sensitivity, inflammation, and energy expenditure.
abstract: The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.
authors.affiliation: Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mansuy-Aubert
authors.forename: Qiong L
authors.initials: QL
authors.lastname: Zhou
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Xie
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Huang
authors.forename: Abdul R
authors.initials: AR
authors.lastname: Khan
authors.forename: Gregory
authors.initials: G
authors.lastname: Aubert
authors.forename: Karla
authors.initials: K
authors.lastname: Candelaria
authors.forename: Shantele
authors.initials: S
authors.lastname: Thomas
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: Shin
authors.forename: Sarah
authors.initials: S
authors.lastname: Booth
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baig
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bilal
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.forename: Fazli R
authors.initials: FR
authors.lastname: Awan
authors.forename: Zhen Y
authors.initials: ZY
authors.lastname: Jiang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000097:blood; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D007473:Ion Channels / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000097:blood* / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D005227:Fatty Acids; C119405:GW 311616; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D010880:Piperidines; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000515:alpha 1-Antitrypsin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D019272:Leukocyte Elastase
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