Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve

Jonathan German, Francis Kim, Gary J. Schwartz, Peter J. Havel, Christopher J. Rhodes, Michael W. Schwartz, Gregory J. Morton

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Abstract

Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fak/fak) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.

Original languageEnglish (US)
Pages (from-to)4502-4511
Number of pages10
JournalEndocrinology
Volume150
Issue number10
DOIs
StatePublished - Oct 2009

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Vagus Nerve
Leptin
Insulin Resistance
Liver
Leptin Receptors
Insulin
Glucose
Insulin Receptor Substrate Proteins
Glucose-6-Phosphatase
Arcuate Nucleus of Hypothalamus
Phosphoenolpyruvate
Vagotomy
Phosphatidylinositol 3-Kinases
Hypothalamus
Signal Transduction
Skeletal Muscle
Phosphotransferases
Hormones
Gene Expression

ASJC Scopus subject areas

  • Endocrinology

Cite this

Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. / German, Jonathan; Kim, Francis; Schwartz, Gary J.; Havel, Peter J.; Rhodes, Christopher J.; Schwartz, Michael W.; Morton, Gregory J.

In: Endocrinology, Vol. 150, No. 10, 10.2009, p. 4502-4511.

Research output: Contribution to journalArticle

German, Jonathan ; Kim, Francis ; Schwartz, Gary J. ; Havel, Peter J. ; Rhodes, Christopher J. ; Schwartz, Michael W. ; Morton, Gregory J. / Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. In: Endocrinology. 2009 ; Vol. 150, No. 10. pp. 4502-4511.
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