Cited by 420Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesAdipokines, Inflammation, and Metabolic Diseases

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PI3K integrates the action of insulin and leptin on hypothalamic neurons

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

DOI 10.1172/jci200524301PMC PMC1062894

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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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Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237
A simplified system for generating recombinant adenoviruses
He, T., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W., & Vogelstein, B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2509 · Cited by 3,209
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Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdán, M. G., Diano, S., Horvath, T. L., Cone, R. D., & Low, M. J. (2001) · Nature · doi:10.1038/35078085 · Cited by 2,356
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Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235
Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality
Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., & Akira, S. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.3801 · Cited by 1,323
Insulin receptors are widely distributed in the central nervous system of the rat
Havránková, J., Roth, J., & Brownstein, M. (1978) · Nature · doi:10.1038/272827a0 · Cited by 1,116
Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons
Woods, S. C., Lotter, E. C., McKay, L. D., & Porte, D. (1979) · Nature · doi:10.1038/282503a0 · Cited by 1,114
Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Stoffel, M., & Friedman, J. M. (1996) · Nature Genetics · doi:10.1038/ng0996-95 · Cited by 1,086

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Wang, J.-H., Wang, F., Yang, M., Yu, D., Wu, W., Liu, J., Ma, L., Cai, F., & Chen, J. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.04.079 · Cited by 66
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Kentish, S. J., & Page, A. J. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.278226 · Cited by 63
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The PI3K signaling pathway mediates the biological effects of leptin.
Donato, J., Frazão, R., & Elias, C. (2010) · Arquivos brasileiros de endocrinologia e metabologia · doi:10.1590/s0004-27302010000700002 · Cited by 53
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Webster, A. N., Becker, J. J., Li, C., Schwalbe, D. C., Kerspern, D., Karolczak, E. O., Bundon, C. B., Onoharigho, R., Crook, M. E., Jalil, M., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01168-8 · Cited by 53
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Levin, B. E., Magnan, C., Migrenne, S., Chua, S. C., & Dunn-Meynell, A. A. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00216.2005 · Cited by 56
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Filippi, B., Abraham, M. A., Yue, J. T. Y., & Lam, T. K. T. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9258-4 · Cited by 43
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Tups, A., Anderson, G., Rizwan, M. Z., Augustine, R. A., Chaussade, C., Shepherd, P., & Grattan, D. (2010) · Journal of neuroendocrinology · doi:10.1111/j.1365-2826.2010.01975.x · Cited by 42

Authors: Xu, A. W.
Affiliations: Stanford Medicine (US)
ORCID: Xu, A. W.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2005-03-10
Volume: 115
Issue: 4
Pages: 951-958
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200524301
PMC: PMC1062894
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: bronze
doi.org
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 › Endocrinology, Diabetes and Metabolism › 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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PI3K integrates the action of insulin and leptin on hypothalamic neurons

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