Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Carvalheira, J. B. C.; Ribeiro, E. B.; Ara�jo, E. P.; Guimar�es, R. B.; Telles, M. M.; Torsoni, M.; Gontijo, J. A. R.; Velloso, L. A.; Saad, M. J. A.

doi:10.1007/s00125-003-1246-x

Cited by 176Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and Cancer

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

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Carvalheira, J. B. C., Ribeiro, E. B., Ara�jo, E. P., Guimar�es, R. B., Telles, M. M., Torsoni, M., Gontijo, J. A. R., Velloso, L. A. +1 more·2003·Diabetologia

DOI 10.1007/s00125-003-1246-x

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Abstract

Aim/hypothesis By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states.Methods Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats.Results Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats.Conclusion/interpretation This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance.

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Both peripheral and central insulin signaling are impaired in obese or diabetic states.
“Both, peripheral and central insulin signaling are impaired in obese or diabetic states.150, 151, 152, 153, 154”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [151]
The Discussion (page unavailable) reports impaired hypothalamic insulin signaling in obese Zucker rats and notes a similar reduction in insulin-receptor phosphorylation in their liver and vascular cells. It does not establish impaired central signaling in diabetic states generally; the hypothalamic impairment studied here is specific to obese Zucker rats. (LLM, conf=0.85)
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Authors: Carvalheira, J. B. C., Ribeiro, E. B., Ara�jo, E. P., Guimar�es, R. B., Telles, M. M., Torsoni, M., Gontijo, J. A. R., Velloso, L. A., & Saad, M. J. A.
Affiliations: Universidade Estadual de Campinas (UNICAMP) (BR)
Universidade Federal de São Paulo (BR)
Corresponding author: Saad, M. J. A.
ORCID: Carvalheira, J. B. C.
Ribeiro, E. B.
Telles, M. M.
Torsoni, M.
Gontijo, J. A. R.
Velloso, L. A.
Saad, M. J. A.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2003-12-01
Volume: 46
Issue: 12
Pages: 1629-1640
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-003-1246-x
OpenAlex: W2038066118
Cited by: 176
References: 68
Citations by year: 2026: 2 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 9 · 2018: 7 · 2017: 14 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 11 · 2012: 17
FWCI: 3.57
Type: journal article
Language: en
Update notices: expression_of_concern (2017-09-14)
erratum (2017-09-14)
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
Funders: Fundação de Amparo à Pesquisa do Estado de São Paulo
Conselho Nacional de Desenvolvimento Científico e Tecnológico
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, hypothalamus, insulin resistance, obesity, Zucker rats, PI3 kinase pathway, MAPK signaling, insulin receptor substrate 2, IRS-1, insulin receptor, Akt phosphorylation, dietary intake
MeSH terms: Animals, Blood Glucose, Body Weight, Hypothalamus, Injections, Intraventricular, Insulin, Male, Obesity, Phosphoproteins, Phosphorylation, Phosphoserine, Rats, Zucker, Reference Values, Signal Transduction, Intracellular Signaling Peptides and Proteins, Rats, Insulin Receptor Substrate Proteins

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Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

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