Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency In Pro-Opiomelanocortin (POMC) Neurons Does Not Enhance Leptin's Anorexigenic Effect, But Improves Glucose Tolerance And Increases Energy Expenditure In Mice Fed A High Fat Diet (Abstract only)

ABERDEIN, Nicola, DO CARMO, Jussara M and HALL, John E (2016). Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency In Pro-Opiomelanocortin (POMC) Neurons Does Not Enhance Leptin's Anorexigenic Effect, But Improves Glucose Tolerance And Increases Energy Expenditure In Mice Fed A High Fat Diet (Abstract only). The FASEB Journal, 30 (1 Supp).

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Official URL: https://www.fasebj.org/doi/abs/10.1096/fasebj.30.1...

Abstract

Obesity is a major cause of Type 2 diabetes (T2D), accounting for 90–95% of all diabetes mellitus, and is closely associated with resistance to the metabolic effects of insulin as well as leptin. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin signalling, has been implicated in the development of obesity-induced leptin and insulin resistance. We previously showed that leptin receptor activation in POMC neurons had powerful antidiabetic effects in non-obese and Type 1 diabetic rodents; whether PTP1B contributes to leptin resistance in POMC neurons in obese subjects is unclear. The objective of this study was to determine whether mice with selective deficiency of PTP1B signalling in POMC neurons have improved glucose regulation and enhanced metabolic responses to hyperleptinemia compared to control mice when fed a normal or high fat diet. Using Cre-loxP technology, PTP1B was deleted specifically in POMC neurons (POMC/PTP1B(−/−)), with PTP1B flox/flox littermates used as controls. Food intake responses to acute leptin (5mg/kg, IP) or saline were measured at 22 weeks of age in mice fed a normal diet. A glucose tolerance test (GTT) was performed at 19 weeks of age. Mice on a normal or high fat diet (HFD – from 6 to 22 weeks of age) were placed in specialized metabolic cages for continuous measurement of oxygen consumption (VO2) and heat production. Mice were infused with leptin for 7 days via IP osmotic minipump (4μg/kg/min). Blood samples were also analyzed for fasting glucose concentration at baseline, on the last day of leptin infusion, and after 7 days of recovery. The anorexigenic effects of leptin over 24 hours were not enhanced in POMC/PTP1B(−/−) mice compared with PTP1Bflox/flox (−1.3±0.3g vs. −1.5±0.2g) fed a normal diet. However, POMC/PTP1B(−/−) mice had decreased fasting blood glucose after chronic leptin infusion when on a HFD (189±6 vs. 135±6 mg/dL) compared to PTP1Bflox/flox (156±25 vs. 151±11 mg/dL). In addition, compared with controls, POMC/PTP1B(−/−) mice had improved glucose tolerance (AUC 27,107±1572 vs. 43,183±5971 mg/dL × 120 min). Chronic leptin infusion increased VO2 in POMC/PTP1B(−/−) mice fed a HFD compared to baseline (96±6 vs. 66±6 ml/kg/min respectively) but this increase was not as pronounced in control mice (97±4 vs. 89±5 ml/kg/min, respectively). Heat production was also increased in POMC/PTP1B(−/−) mice on a HFD during chronic leptin infusion (783±96 vs. 586±58 Cal/hr) but no change was observed in control mice (743±39 vs. 764±13 Cal/hr). These results demonstrate that PTP1B deficiency in POMC neurons does not enhance the anorexigenic effects of leptin in mice fed a normal diet. However PTP1B deficiency in POMC neurons improves glucose regulation in obese mice fed a HFD. Furthermore, POMC PTP1B deficient mice also demonstrated increased VO2 and heat production compared with controls during chronic hyperleptinemia. PTP1B could be an important drug target for T2D treatment via its effects to attenuate obesity-induced leptin resistance.

Item Type: Article
Uncontrolled Keywords: 0601 Biochemistry And Cell Biology; 0606 Physiology; 1116 Medical Physiology; Biochemistry & Molecular Biology
SWORD Depositor: Symplectic Elements
Depositing User: Symplectic Elements
Date Deposited: 10 Apr 2019 10:23
Last Modified: 26 Sep 2023 02:02
URI: https://shura.shu.ac.uk/id/eprint/23291

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