Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance

Am J Physiol Regul Integr Comp Physiol. 2018 Mar 1;314(3):R478-R488. doi: 10.1152/ajpregu.00287.2017. Epub 2017 Dec 20.


Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signaling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signaling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of proopiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high-fat diet (HFD). When compared with control mice (PTP1B flox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1B flox/flox/POMC-Cre) had attenuated body weight gain (males: -18%; females: -16%) and fat mass (males: -33%; female: -29%) in response to HFD. Glucose tolerance was improved by 40%, and liver lipid accumulation was reduced by 40% in PTP1B/POMC-Cre males but not in females. When compared with control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (males: 112 ± 1 vs. 112 ± 1 mmHg in controls; females: 106 ± 3 vs. 109 ± 3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in males or females compared with control mice (males: Δ32 ± 0 vs. Δ29 ± 4 mmHg; females: Δ22 ± 2 vs. Δ27 ± 4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice and attenuated weight gain in males and females but did not enhance the MAP and HR responses to a HFD or to acute stress.

Keywords: blood pressure; glucose; leptin; lipid; liver; obesity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / enzymology*
  • Arcuate Nucleus of Hypothalamus / physiopathology
  • Biomarkers / blood
  • Blood Glucose / metabolism*
  • Diet, High-Fat
  • Disease Models, Animal
  • Female
  • Glucose Intolerance / blood
  • Glucose Intolerance / enzymology*
  • Glucose Intolerance / physiopathology
  • Glucose Intolerance / prevention & control
  • Lipid Metabolism*
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / enzymology*
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Obesity / enzymology*
  • Obesity / etiology
  • Obesity / physiopathology
  • Obesity / prevention & control
  • Pro-Opiomelanocortin / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Sex Factors
  • Solitary Nucleus / enzymology*
  • Solitary Nucleus / physiopathology
  • Weight Gain


  • Biomarkers
  • Blood Glucose
  • Pro-Opiomelanocortin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse