Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2011-05, Vol.57 (5), p.918-926
• Main Authors: do Carmo, Jussara M, da Silva, Alexandre A, Cai, Zhengwei, Lin, Shuying, Dubinion, John H, Hall, John E
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Appetite - drug effects; Appetite - physiology; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood Pressure - drug effects; Blood Pressure - physiology; Body Weight - drug effects; Body Weight - physiology; Eating - drug effects; Eating - physiology; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Immunohistochemistry; Insulin - blood; Leptin - metabolism; Leptin - pharmacology; Male; Mice; Mice, Knockout; Motor Activity - drug effects; Motor Activity - physiology; Neurons - drug effects; Neurons - metabolism; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Pro-Opiomelanocortin - metabolism; Receptors, Leptin - genetics; Receptors, Leptin - metabolism; Telemetry
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hypertensionaha.110.161349

Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR(flox/flox)/POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR(flox/flox)/POMC-Cre, wild-type, LepR(flox/flox), and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR(flox/flox)/POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR(flox/flox), and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR(flox/flox)/POMC-Cre mice had normal MAP and heart rate compared with LepR(flox/flox) but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR(flox/flox)/POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR(flox/flox)/POMC-Cre mice. Leptin increased oxygen consumption in LepR(flox/flox)/POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption.