Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency in Proopiomelanocortin (POMC) Neurons Attenuates Body Weight, Fat Mass and Liver Lipid Accumulation in Mice Fed a High Fat Diet

Leptin acts on the central nervous system (CNS) to reduce appetite and body weight, improve glucose regulation, and increase energy expenditure and sympathetic nervous system (SNS) activity. Central leptin has also been shown to exert antisteatotic effects on non-adipose tissues. However, in severe obesity there may be resistance to leptin’s anorexic, antidiabetic and antisteatotic effects but sustained effects to increase SNS activity, blood pressure (BP), and heart rate (HR). Our previous studies showed that POMC neurons are important for mediating the BP, HR and glucose effects of leptin but the role of POMC neurons in mediating leptin’s effects on liver lipid accumulation remain less well defined. In this study we examined if deleting PTP1B, a negative regulator of leptin signaling, specifically in POMC neurons or in the entire forebrain, would protect mice against the adverse metabolic effects of a high fat diet (HFD). Male and female mice with forebrain (PTP1Bflox/flox/CamK2R5-Cre) or POMC specific (PTP1Bflox/flox/POMC-Cre) PTP1B deficiency and littermate controls (PTP1Bfox/flox) were fed a HFD from 6–20 weeks of age. Compared to PTP1Bflox/flox mice, mice with PTP1B deficiency in POMC neurons or in the entire forebrain had reduced body weight gain between 6 and 20 weeks of age when fed a HFD (Δ19.1 ±1.7g vs. Δ13.7±1.1g and Δ15.3±1.4g, respectively), and attenuated increase in fat mass (Δ13.3±1.2g vs. Δ7.3±0.7g and Δ10.2±1.0g, respectively). PTP1B deficiency attenuated food intake in forebrain specific PTP1B deficient mice compared to PTP1Bflox/flox and POMC specific PTP1B deficient mice (2.0±0.1g, 2.7±0.1g and 2.5±0.1 g, respectively). Glucose tolerance, expressed as area under the curve (AUC), was improved by PTP1B deficiency in forebrain and POMC specific neurons compared to PTP1Bflox/flox mice fed a HFD (AUC 19016±1172, 23207±1534 and 27561±3088, respectively). Liver fat mass, assessed by EchoMRI at 29±0.5 weeks of age, was reduced and liver lean mass was increased in mice with PTP1B deficiency in POMC neurons or in the entire forebrain (Fat: 8.8±1.8 and 6.0±3.3 mg/g, Lean: 93.6±2.8 and 97.2±5.6 mg/g, respectively) compared to PTP1Bflox/flox mice (Fat: 14.2±2., Lean: 79.4±10.3 mg/g), indicating a healthier liver profile. These findings indicate that PTP1B signaling in POMC neurons plays an important role in regulating body weight, fat mass, glucose tolerance and liver lipid accumulation in response to a chronic HFD but effects of PTP1B on food intake are mediated mainly in forebrain neurons other than POMC.