Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons.
To investigate whether phosphatidylinositol-3 kinase (PI3K) signaling mediates the metabolic effects of hypothalamic leptin action, adenoviral gene therapy was used to direct expression of leptin receptors to the area of the hypothalamic arcuate nucleus (ARC). This intervention markedly improved insulin sensitivity in genetically obese, leptin-receptor-deficient Koletsky (fa(k)/fa(k)) rats via a mechanism that was not dependent on reduced food intake but was attenuated by approximately 44% by third-ventricular infusion of the PI3K inhibitor LY294002. Conversely, ARC-directed expression of a constitutively active mutant of protein kinase B (PKB/Akt, an enzyme activated by PI3K) mimicked the insulin-sensitizing effect of restored hypothalamic leptin signaling in these animals, despite having no effect on food intake or body weight. These findings suggest that hypothalamic leptin signaling is an important determinant of glucose metabolism and that the underlying neuronal mechanism involves PI3K.
Morton
Gregory J
GJ
Department of Medicine, Harborview Medical Center and University of Washington, Seattle, WA 98104, USA.
Gelling
Richard W
RW
Niswender
Kevin D
KD
Morrison
Christopher D
CD
Rhodes
Christopher J
CJ
Schwartz
Michael W
MW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000473:pathology*; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; D002867:Chromones; D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D009025:Morpholines; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D049452:Green Fluorescent Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose