PI3K integrates the action of insulin and leptin on hypothalamic neurons
Allison Wanting Xu, … , Michael W. Schwartz, Gregory S. Barsh
Allison Wanting Xu, … , Michael W. Schwartz, Gregory S. Barsh
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):951-958. https://doi.org/10.1172/JCI24301.
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Article Metabolism

PI3K integrates the action of insulin and leptin on hypothalamic neurons

Abstract

Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores. Leptin and insulin have been implicated as circulating indicators of adiposity, but it is not clear how changes in their levels are perceived or integrated by individual neuronal subtypes. We developed mice in which a fluorescent reporter for PI3K activity is targeted to either Agrp or POMC neurons and used 2-photon microscopy to measure dynamic regulation of PI3K by insulin and leptin in brain slices. We show that leptin and insulin act in parallel to stimulate PI3K in POMC neurons but in opposite ways on Agrp neurons. These results suggest a new view of hypothalamic circuitry, in which the effects of leptin and insulin are integrated by anorexigenic but not by orexigenic neurons.

Authors

Allison Wanting Xu, Christopher B. Kaelin, Kiyoshi Takeda, Shizuo Akira, Michael W. Schwartz, Gregory S. Barsh

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Figure 1

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Generating PomcCre, AgrpCre transgenic mice, and neuron-specific Stat3 k...
Generating PomcCre, AgrpCre transgenic mice, and neuron-specific Stat3 knockout mice. (A) Transgene diagrams in which blue and red boxes represent protein-coding regions for the Pomc and Agrp genes, respectively. (B) Schematic representation of the Rosa26 reporter (top) and Stat3 (bottom). (C) X-gal staining of brain sections through the arcuate nucleus from transgenic R26R+ mice. (D) X-gal staining (blue) combined with immunohistochemistry (brown) for α-MSH and Agrp; neuropeptide immunostaining is distributed throughout neuronal cell bodies and also in some terminals; X-gal staining is a localized precipitate within the neuronal cytoplasm.