Protein tyrosine phosphatase 1b (Ptp1b) is a negative regulator of leptin and insulin-signalling pathways. Its targeted deletion in proopiomelanocortin (POMC) neurons protects mice from obesity and diabetes by increasing energy expenditure. Inflammation accompanies increased energy expenditure. Therefore, the present study aimed to determine whether POMC-Ptp1b deletion increases energy expenditure via an inflammatory process, which would impair endothelial function. We characterized the metabolic and cardiovascular phenotypes of Ptp1b+/+ and POMC-Ptp1b−/− mice. Clamp studies revealed that POMC-Ptp1b deletion reduced body fat and increased energy expenditure as evidenced by a decrease in feed efficiency and an increase in oxygen consumption and respiratory exchange ratio. POMC-Ptp1b deletion induced a 2.5-fold increase in plasma tumour necrosis factor α (TNF-α) levels and elevated body temperature. Vascular studies revealed an endothelial dysfunction in POMC-Ptp1b−/− mice. Nitric oxide synthase inhibition [N-nitro-L-arginine methyl ester (L-NAME)] reduced relaxation to a similar extent in Ptp1b+/+ and POMC-Ptp1b−/− mice. POMC-Ptp1b deletion decreased ROS-scavenging enzymes [superoxide dismutases (SODs)] whereas it increased ROS-generating enzymes [NADPH oxidases (NOXs)] and cyclooxygenase-2 (COX-1) expression, in aorta. ROS scavenging or NADPH oxidase inhibition only partially improved relaxation whereas COX-2 inhibition and thromboxane-A2 (TXA2) antagonism fully restored relaxation in POMC-Ptp1b−/− mice. Chronic treatment with the soluble TNF-α receptor etanercept decreased body temperature, restored endothelial function and reestablished aortic COX-2, NOXs and SOD expression to their baseline levels in POMC-Ptp1b−/− mice. However, etanercept promoted body weight gain and decreased energy expenditure in POMC-Ptp1b−/− mice. POMC-Ptp1b deletion increases plasma TNF-α levels, which contribute to body weight regulation via increased energy expenditure and impair endothelial function via COX-2 and ROS-dependent mechanisms.
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June 2016
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Mitochondrial protein quality control plays a decisive role in the maintenance of a proper mitochondrial function in metabolically active tissues such as skeletal muscle. Several chaperones and proteases, involved in the regulation of mitochondrial protein quality control, are altered in obesity and type 2 diabetes mellitus. For further details see Dahlmans et al. pp. 843–852.
Research Article|
April 22 2016
Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms
Thiago Bruder-Nascimento;
Thiago Bruder-Nascimento
*Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
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Simone Kennard;
Simone Kennard
*Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
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Galina Antonova;
Galina Antonova
*Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
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James D. Mintz;
James D. Mintz
†Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, U.S.A.
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Kendra K. Bence;
Kendra K. Bence
‡Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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Eric J. Belin de Chantemèle
*Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
Correspondence: Eric J. Belin de Chantemèle (email [email protected]).
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Publisher: Portland Press Ltd
Received:
September 29 2015
Revision Received:
February 29 2016
Accepted:
March 01 2016
Accepted Manuscript online:
March 02 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (11): 881–893.
Article history
Received:
September 29 2015
Revision Received:
February 29 2016
Accepted:
March 01 2016
Accepted Manuscript online:
March 02 2016
Citation
Thiago Bruder-Nascimento, Simone Kennard, Galina Antonova, James D. Mintz, Kendra K. Bence, Eric J. Belin de Chantemèle; Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms. Clin Sci (Lond) 1 June 2016; 130 (11): 881–893. doi: https://doi.org/10.1042/CS20160073
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