PI3K integrates the action of insulin and leptin on hypothalamic neurons
Allison Wanting Xu, Christopher B. Kaelin, Kiyoshi Takeda, Shizuo Akira, Michael W. Schwartz, Gregory S. Barsh
Allison Wanting Xu, Christopher B. Kaelin, Kiyoshi Takeda, Shizuo Akira, Michael W. Schwartz, Gregory S. Barsh
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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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PI3K activation in POMC neurons does not require Stat3 function. (A) Rep...
PI3K activation in POMC neurons does not require Stat3 function. (A) Representative Stat3-deficient POMC neuron exposed to 100 nM leptin, in which membrane localization of PI3K reporter protein occurs within several minutes of hormone addition. Arrows indicate membrane localization. (B) Percentage of POMC neurons responsive to leptin in the presence (+/+) or absence (–/–) of Stat3. (C) Unifying mechanism for leptin modulation of key arcuate nucleus neurons in which PI3K activity is a mediator and/or marker of neuronal activation and neuropeptide release in both Agrp (pink) and POMC (green) neurons. The effects of insulin on PI3K activity are direct in both neuronal subtypes, but the effects of leptin on PI3K activity in Agrp neurons require synaptic transmission from POMC or other (gray) inhibitory presynaptic neurons. IR, insulin receptor; LepR, leptin receptor.