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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Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621
Generalized lacZ expression with the ROSA26 Cre reporter strain
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
Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
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
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
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
Ablation of Insulin-Producing Neurons in Flies: Growth and Diabetic Phenotypes
Rulifson, E. J., Kim, S. K., & Nusse, R. (2002) · Science · doi:10.1126/science.1070058 · Cited by 1,064
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Bates, S. H., Stearns, W. H., Dundon, T. A., Schubert, M., Tso, A. W. K., Wang, Y., Banks, A. S., Lavery, H. J., Haq, A. K., Maratos-Flier, E., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010 · cited 2×
“In addition, work of Myers and colleagues (6) has shown that animals carrying a modified leptin receptor that cannot activate Stat3, Lepr1138Ser, develop a subset of the same phenotypic abnormalities caused by a null Lepr allele; thus, it will be interesting to examine the effects of leptin on PI3K activation and elec…”
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Pinto, S., Roseberry, A. G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J. M., & Horvath, T. L. (2004) · Science · doi:10.1126/science.1089459 · Cited by 987
Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis
Balthasar, N., Coppari, R., McMinn, J., Liu, S. M., Lee, C. E., Tang, V., Kenny, C. D., McGovern, R. A., Chua, S. C., Elmquist, J. K., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.004 · Cited by 935
Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area
Elias, C. F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R. S., Bjorbæk, C., Flier, J. S., Saper, C. B., & Elmquist, J. K. (1999) · Neuron · doi:10.1016/s0896-6273(01)80035-0 · Cited by 924
Activation of Downstream Signals by the Long Form of the Leptin Receptor
Banks, A. S., Davis, S. M., Bates, S. H., & Myers, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14563 · Cited by 797
Regulation of C. elegans Life-Span by Insulinlike Signaling in the Nervous System
Wolkow, C. A., Kimura, K. D., Lee, M. S., & Ruvkun, G. (2000) · Science · doi:10.1126/science.290.5489.147 · Cited by 681
Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., & Ashford, M. L. J. (1997) · Nature · doi:10.1038/37379 · Cited by 628
Correction: Stat3 Activation Is Responsible for IL-6–Dependent T Cell Proliferation through Preventing Apoptosis: Generation and Characterization of T Cell–Specific Stat3-Deficient Mice
Takeda, K., Kaisho, T., Yoshida, N., Takeda, J., Kishimoto, T., & Akira, S. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500168 · Cited by 617
Key enzyme in leptin-induced anorexia
Niswender, K. D., Morton, G. J., Stearns, W. H., Rhodes, C. J., Myers, M. G., & Schwartz, M. W. (2001) · Nature · doi:10.1038/35101657 · Cited by 585
Stat3 Activation Is Responsible for IL-6-Dependent T Cell Proliferation Through Preventing Apoptosis: Generation and Characterization of T Cell-Specific Stat3-Deficient Mice
Takeda, K., Kaisho, T., Yoshida, N., Takeda, J., Kishimoto, T., & Akira, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4652 · Cited by 584
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Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert, M., Brazil, D. P., Burks, D. J., Kushner, J. A., Ye, J., Flint, C. L., Farhang-Fallah, J., Dikkes, P., Warot, X. M., Rio, C., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07084.2003 · Cited by 488
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Niswender, K. D., Morrison, C. D., Clegg, D. J., Olson, R., Baskin, D. G., Myers, M. G., Seeley, R. J., & Schwartz, M. W. (2003) · Diabetes · doi:10.2337/diabetes.52.2.227 · Cited by 476
Leptin Receptor Signaling and the Regulation of Mammalian Physiology
Myers, M. G. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.287 · Cited by 463
Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus
Mercer, J. G., Hoggard, N., Williams, L. M., Lawrence, C. B., Hannah, L. T., Morgan, P. J., & Trayhurn, P. (1996) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1996.05161.x · Cited by 460
Genetic approaches to studying energy balance: perception and integration
Barsh, G. S., & Schwartz, M. W. (2002) · Nature Reviews Genetics · doi:10.1038/nrg862 · Cited by 438
Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus
van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M., & Spanswick, D. (2004) · Nature Neuroscience · doi:10.1038/nn1226 · Cited by 435
Specificity and promiscuity in phosphoinositide binding by pleckstrin homology domains
Kavran, J. M., Klein, D. E., Lee, A., Falasca, M., Isakoff, S. J., Skolnik, E. Y., & Lemmon, M. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.46.30497 · Cited by 434
DNA cloning by homologous recombination in Escherichia coli
Zhang, Y., Muyrers, J. P. P., Testa, G., & Stewart, A. F. (2000) · Nature Biotechnology · doi:10.1038/82449 · Cited by 433
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Klarlund, J. K., Guilherme, A., Holik, J. J., Virbasius, J. V., Chawla, A., & Czech, M. (1997) · Science · doi:10.1126/science.275.5308.1927 · Cited by 415
Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation
Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I., & Fu, X.-Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0303992101 · Cited by 385
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Challis, B., Coll, A. P., Yeo, G. S. H., Pinnock, S. B., Dickson, S. L., Thresher, R. R., Dixon, J. B., Zahn, D., Rochford, J. J., White, A. E., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0306931101 · Cited by 376
Hypothalamic Proopiomelanocortin Neurons Are Glucose Responsive and Express KATPChannels
Ibrahim, N., Bosch, M. A., Smart, J. L., Qiu, J., Rubinstein, M., Rønnekleiv, O. K., Low, M. J., & Kelly, M. J. (2003) · Endocrinology · doi:10.1210/en.2002-221033 · Cited by 355
Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus.
Baskin, D. G., Breininger, J. F., & Schwartz, M. W. (1999) · Diabetes · doi:10.2337/diabetes.48.4.828 · Cited by 351
Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin
Münzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C. (2003) · Endocrinology · doi:10.1210/en.2002-221037 · Cited by 328
Does insulin dysfunction play a role in Alzheimer's disease?
Gasparini, L. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02037-0 · Cited by 314
STAT3 as an Adapter to Couple Phosphatidylinositol 3-Kinase to the IFNAR1 Chain of the Type I Interferon Receptor
Pfeffer, L. M., Mullersman, J. E., Pfeffer, S. R., Murti, A., Shi, W., & Yang, C. H. (1997) · Science · doi:10.1126/science.276.5317.1418 · Cited by 258
The dopamine β-hydroxylase gene promoter directs expression of E. coli lacZ to sympathetic and other neurons in adult transgenic mice
Mercer, E. H., Hoyle, G. W., Kapur, R. P., Brinster, R. L., & Palmiter, R. D. (1991) · Neuron · doi:10.1016/0896-6273(91)90274-4 · Cited by 247
A phosphatidylinositol 3-kinase–phosphodiesterase 3B–cyclic AMP pathway in hypothalamic action of leptin on feeding
Zhao, A. Z., Huan, J.-N., Gupta, S., Pal, R., & Sahu, A. (2002) · Nature Neuroscience · doi:10.1038/nn885 · Cited by 242
PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane
Viard, P., Butcher, A. J., Halet, G., Davies, A., Nürnberg, B., Heblich, F., & DOLPHIN, A. C. (2004) · Nature Neuroscience · doi:10.1038/nn1300 · Cited by 241
Monitoring of stored and available fuel by the CNS: implications for obesity
Seeley, R. J., & Woods, S. C. (2003) · Nature reviews. Neuroscience · doi:10.1038/nrn1245 · Cited by 233
Physiological and Anatomical Circuitry between Agouti-Related Protein and Leptin Signaling
Wilson, B. D., Bagnol, D., Kaelin, C. B., Ollmann, M. M., Gantz, I., Watson, S. J., & Barsh, G. S. (1999) · Endocrinology · doi:10.1210/endo.140.5.6728 · Cited by 203
Now you see it...
Jones, R. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn902 · Cited by 184
Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus - relationship with NPY neurones
Håkansson, M., Hulting, A., & Meister, B. (1996) · Neuroreport · doi:10.1097/00001756-199611250-00059 · Cited by 167
GABA Release from Proopiomelanocortin Neurons
Hentges, S. T., Nishiyama, M., Overstreet‐Wadiche, L., Stenzel‐Poore, M. P., Williams, J. T., & Low, M. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3952-03.2004 · Cited by 162
Essential Role of STAT3 in Body Weight and Glucose Homeostasis
Cui, Y., Huang, L., Elefteriou, F., Yang, G., Shelton, J. M., Giles, J. E., Öz, O. K., Pourbahrami, T., Lu, C. Y., Richardson, J. A., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.1.258-269.2004 · Cited by 144
Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats.
Havel, P. J., Hahn, T. M., Sindelar, D. K., Baskin, D. G., Dallman, M. F., Weigle, D. S., & Schwartz, M. W. (2000) · Diabetes · doi:10.2337/diabetes.49.2.244 · Cited by 136
Direct Activation of the Epithelial Na+ Channel by Phosphatidylinositol 3,4,5-Trisphosphate and Phosphatidylinositol 3,4-Bisphosphate Produced by Phosphoinositide 3-OH Kinase
Tong, Q., Gamper, N. L., Medina, J., Shapiro, M. S., & Stockand, J. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401004200 · Cited by 102
Identification of the Critical Sequence Elements in the Cytoplasmic Domain of Leptin Receptor Isoforms Required for Janus Kinase/Signal Transducer and Activator of Transcription Activation by Receptor Heterodimers
Bahrenberg, G., Behrmann, I., Barthel, A., Hekerman, P., Heinrich, P. C., Joost, H., & Becker, W. B. (2002) · Molecular Endocrinology · doi:10.1210/mend.16.4.0800 · Cited by 102
Leptin Receptor and Neuropeptide Y Gene Expression in the Sheep Brain
Williams, Ádám, Mercer, Moar, Slater, Hunter, L., Findlay, & Hoggard, N. (1999) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1999.00293.x · Cited by 75
Calmodulin Antagonists Inhibit Insulin-Stimulated GLUT4 (Glucose Transporter 4) Translocation by Preventing the Formation of Phosphatidylinositol 3,4,5-Trisphosphate in 3T3L1 Adipocytes
Yang, C., Watson, R. T., Elmendorf, J. S., Sacks, D. B., & Pessin, J. E. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.2.0425 · Cited by 56
Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin‐induced diabetic rats
Hidaka, S., Yoshimatsu, H., Kondou, S., Oka, K., Tsuruta, Y., Sakino, H., Itateyama, E., Noguchi, H., Himeno, K., Okamoto, K., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00317.x · Cited by 33

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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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