Cited by 421Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesAdipokines, Inflammation, and Metabolic Diseases

PI3K integrates the action of insulin and leptin on hypothalamic neurons

Open access
Xu, A. W.·2005·Journal of Clinical Investigation

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.

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Registry

Crossref · 10.1172/jci200524301

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  • Leptin inhibits the firing rate of NPY/AgRP neurons, depolarizes POMC neurons, and activates PI3K signaling in POMC cells.

    “leptin inhibits the firing rate of NPY/AgRP neurons (189), while simultaneously depolarizing POMC neurons (42), and also activates PI3K signaling in the latter cells (204).”
  • Insulin hyperpolarizes and silences both AgRP and POMC neurons and activates PI3K signaling in both.

    “insulin hyperpolarizes and silences both AgRP and POMC neurons (96) and activates PI3K signaling in both these neuronal populations (204).”

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Authors
Xu, A. W.
Affiliations
Stanford Medicine (US)
Venue
Journal of Clinical Investigation
Published
2005-03-10
Volume
115
Issue
4
Pages
951-958
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2161418574
Cited by
420
References
54
Citations by year
2026: 2 · 2025: 10 · 2024: 8 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 7 · 2019: 18 · 2018: 17 · 2017: 24 · 2016: 20 · 2015: 18 · 2014: 24 · 2013: 27 · 2012: 27
FWCI
12.61
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • School of Medicine, Stanford University
  • Stanford Bio-X
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-48506, R01DK048506, P01DK068384, DK-68384)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
PI3K signaling, insulin, leptin, hypothalamic neurons, proopiomelanocortin neurons, energy balance, appetite regulation, anorexigenic neurons, orexigenic neurons, neuronal activity imaging
MeSH terms
Animals, Energy Metabolism, Enzyme Activation, Homeostasis, Hypothalamus, Insulin, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Neurons, Pro-Opiomelanocortin, Proteins, Recombinant Fusion Proteins, Gene Expression Regulation, Enzymologic, Genes, Reporter, Mice, Knockout, Microscopy, Confocal, Phosphatidylinositol 3-Kinases, Leptin, Intercellular Signaling Peptides and Proteins, Mice, Agouti-Related Protein

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