Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels.
Leptin, the protein encoded by the obese (ob) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight. It has been proposed that leptin acts in the hypothalamus, the main control centre for satiety and energy expenditure. Mutations in leptin or the receptor isoform (Ob-R[L]) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague-Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (K[ATP]) channel. Our data indicate that the K(ATP) channel may function as the molecular end-point of the pathway following leptin activation of the Ob-R(L) receptor in hypothalamic neurons.
Spanswick
D
D
Department of Biomedical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, UK.
Smith
M A
MA
Groppi
V E
VE
Logan
S D
SD
Ashford
M L
ML
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism*; D066298:In Vitro Techniques; D020738:Leptin; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D014044:Tolbutamide / Q000494:pharmacology
D007004:Hypoglycemic Agents; D020738:Leptin; D015221:Potassium Channels; D011506:Proteins; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005947:Glucose