Insulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus
Abstract
In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. In the hypothalamus, insulin functions with leptin as an afferent adiposity signal important for the regulation of body fat stores and hepatic glucose metabolism. To test the hypothesis that hypothalamic insulin action involves intracellular PI3K signaling, we used histochemical and biochemical methods to determine the effect of insulin on hypothalamic IRS-PI3K activity. Here, we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K, and activates protein kinase B/Akt, a downstream target of PI3K. Using an immunohistochemical technique to detect PI 3,4,5-triphosphate, the main product of PI3K activity, we further demonstrate that in the arcuate nucleus, insulin-induced PI3K activity occurs preferentially within cells that contain IRS-2. Finally, we show that the food intake- lowering effects of insulin are reversed by intracerebroventricular infusion of either of two PI3K inhibitors at doses that have no independent feeding effects. These findings support the hypothesis that the IRS-PI3K pathway is a mediator of insulin action in the arcuate nucleus and, combined with recent evidence that leptin activates PI3K signaling in the hypothalamus, provide a plausible mechanism for neuronal cross-talk between insulin and leptin signaling.
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Like insulin, leptin activates the IRS-PI3K pathway in the hypothalamus, and pharmacological inhibition of PI3K in the brain blocks leptin's ability to reduce food intake.
“like insulin, leptin activates the IRS-PI3K pathway in the hypothalamus, and pharmacological inhibition of PI3K activity in the brain blocks the ability of leptin to reduce food intake (129, 130).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [129]
PI3K is required for insulin to inhibit food intake.
“PI3K is also required for the ability of insulin to inhibit food intake (129).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [129]
Insulin activates the IRS-PI3K pathway in hypothalamic neurons.
“Like leptin, insulin also activates the IRS-PI3K pathway in hypothalamic neurons”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [129]
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- Authors
- Niswender, K. D., Morrison, C. D., Clegg, D. J., Olson, R., Baskin, D. G., Myers, M. G., Seeley, R. J., & Schwartz, M. W.
- Affiliations
- University of Washington (US)
- University of Cincinnati (US)
- Joslin Diabetes Center (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2003-02-01
- Volume
- 52
- Issue
- 2
- Pages
- 227-231
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2102743478
- Cited by
- 476
- References
- 28
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 2 · 2023: 7 · 2022: 2 · 2021: 22 · 2020: 15 · 2019: 22 · 2018: 13 · 2017: 19 · 2016: 24 · 2015: 14 · 2014: 23 · 2013: 22 · 2012: 32
- FWCI
- 13.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (2r01dk012829-36)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731, DK 12829, T32-DK-07247, R01DK052989, DK-52989, R01DK054890, DK-17047, DK-54890, P30DK017047, T32DK007247)
- National Institute of Neurological Disorders and Stroke (NS-32273)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin signaling, phosphatidylinositol 3-kinase, IRS-1, insulin receptor substrate 2, hypothalamic arcuate nucleus, Akt/protein kinase B, insulin receptor tyrosine phosphorylation, food intake regulation, leptin signaling, hepatic glucose metabolism
- MeSH terms
- Animals, Anorexia, Arcuate Nucleus of Hypothalamus, Disease Models, Animal, Enzyme Activation, Insulin, Rats, Wistar, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylinositol 3-Kinases, Rats
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