title: Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms.
abstract: 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.
authors.affiliation: Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Thiago
authors.initials: T
authors.lastname: Bruder-Nascimento
authors.affiliation: Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Simone
authors.initials: S
authors.lastname: Kennard
authors.affiliation: Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Galina
authors.initials: G
authors.lastname: Antonova
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: James D
authors.initials: JD
authors.lastname: Mintz
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Bence
authors.affiliation: Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, U.S.A. ebelindechanteme@gru.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; C026512:arginine methyl ester; D011333:Pro-Opiomelanocortin; D001120:Arginine; D051546:Cyclooxygenase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: COX-2; Ptp1b; endothelium; energy expenditure; inflammation