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.