Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms

Thiago Bruder-Nascimento, Simone Kennard, Galina Antonova, James D. Mintz, Kendra K. Bence, Eric Jacques Belin de Chantemele

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)881-893
Number of pages13
JournalClinical Science
Volume130
Issue number11
DOIs
StatePublished - Jan 1 2016

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Pro-Opiomelanocortin
Energy Metabolism
Tumor Necrosis Factor-alpha
Neurons
NADPH Oxidase
Body Temperature
Superoxide Dismutase
Body Weight
Thromboxane A2
Tumor Necrosis Factor Receptors
NG-Nitroarginine Methyl Ester
Enzymes
Cyclooxygenase 2

Keywords

  • COX-2
  • Endothelium
  • Energy expenditure
  • Inflammation
  • Ptp1b

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms. / Bruder-Nascimento, Thiago; Kennard, Simone; Antonova, Galina; Mintz, James D.; Bence, Kendra K.; Belin de Chantemele, Eric Jacques.

In: Clinical Science, Vol. 130, No. 11, 01.01.2016, p. 881-893.

Research output: Contribution to journalArticle

Bruder-Nascimento, Thiago ; Kennard, Simone ; Antonova, Galina ; Mintz, James D. ; Bence, Kendra K. ; Belin de Chantemele, Eric Jacques. / Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms. In: Clinical Science. 2016 ; Vol. 130, No. 11. pp. 881-893.
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