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Effect of Intracerebroventricular Insulin Infusion on Diabetic Hyperphagia and Hypothalamic Neuropeptide Gene Expression
Abstract
To test the hypothesis that diabetic hyperphagia results from insulin deficiency in the brain, diabetic rats (streptozotocin-induced) were given an intracerebroventricular (ICV) infusion of saline or insulin (at a dose that did not affect plasma glucose levels) for 6 days. Food and water intake were significantly increased in diabetic rats, but only food intake was affected by ICV insulin. Diabetic hyperphagia was reduced 58% by ICV insulin compared with ICV saline (P < 0.05) and was accompanied by a 69% increase in diabetes-induced weight loss (P < 0.05). To evaluate whether central nervous system (CNS) insulin deficiency affects expression of neuropeptides involved in food intake, in situ hybridization was done for neuropeptide Y (NPY), which stimulates feeding, in the hypothalamic arcuate nucleus and for cholecystokinin (CCK) and corticotropin-releasing hormone (CRH), which inhibit feeding, in the hypothalamic paraventricular nucleus. In diabetic rats, NPY mRNA hybridization increased 280% (P < 0.05), an effect reduced 40% by ICV insulin (P < 0.05). CCK mRNA hybridization increased 50% in diabetic rats (P < 0.05), a response reduced slightly by ICV insulin (P < 0.05), whereas CRH mRNA hybridization decreased 33% in diabetic rats (P < 0.05) and was unchanged by ICV insulin. The results demonstrate that CNS infusion of insulin to diabetic rats reduces both hyperphagia and overexpression of hypothalamic NPY mRNA. This observation supports the hypothesis that a deficiency of insulin in the brain is an important cause of diabetic hyperphagia and that increased hypothalamic NPY gene expression contributes to this phenomenon.
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“deficiency of either hormone or their respective receptors in the CNS results in hyperphagia, weight gain and insulin resistance (27, 174, 183, 212).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [174]
In the citing paper
“icv infusion of insulin at a dose that attenuates diabetic hyperphagia fails to normalize blood glucose levels in STZ-diabetic rats (36)”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [36]
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Hypoleptinemia, but not hypoinsulinemia, induces hyperphagia in streptozotocin‐induced diabetic rats
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“STZ-DM rodents with hypoleptinemia but hypoinsulinemia were found to have their neuropeptide up-regulated, similar to genetically obese models (Williams et al. 1988; White et al. 1990; Sipols et al. 1995; Havel et al. 2000).”
MethodResultPlasma neuropeptide Y levels differ in distinct diabetic conditions
İlhan, A., Rasul, S., Dimitrov, A., Handisurya, A., Gärtner, W., Baumgartner-Parzer, S. M., Wagner, L., Kautzky‐Willer, A., & Base, W. (2010) · Neuropeptides · doi:10.1016/j.npep.2010.08.001 · Cited by 34
“In diabetic rats, NPY expression in hypothalamic regions was enhanced, whereas after insulin injection its expression was decreased (Sipols et al., 1995).”
BackgroundInsulin signalling in hypothalamic neurones
Belsham, D. D., & Dalvi, P. S. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12919 · Cited by 35
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Self-citationThe Role of Neuropeptide Y in Energy Homeostasis
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Hypothalamic Lipids and the Regulation of Energy Homeostasis
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“Insulin, like leptin, is a hormone involved in the regulation of bodyweight, glucose homeostasis, and is also a necessary signal to support normal reproductive function and energy homeostasis [66–75].”
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“Elevated hypothalamic NPY tone (with a concomitant reduction of proopiomelanocortin (POMC) tone) is associated with obesity and diabetes in rodent models [19,20] and humans [21e23] due to defects in inhibitory feedback signaling to the CNS [24,25].”
Metabolic syndrome is a low-grade systemic inflammatory condition
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Physiological Mechanisms Integrating Metabolism and Reproduction
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Neuroendocrine regulation of food intake
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“The next question, then, is how the CNS is made aware of the status of body energy stores.”
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Metadata
- Authors
- Sipols, A. J., Baskin, D. G., & Schwartz, M. W.
- Affiliations
- University of Washington (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1995-02-01
- Volume
- 44
- Issue
- 2
- Pages
- 147-151
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2099542131
- Cited by
- 389
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 14 · 2017: 11 · 2016: 14 · 2015: 6 · 2014: 13 · 2013: 16 · 2012: 15
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (2r01dk012829-36)
- Diabetes Research Center, University of Washington
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, DK17844, DK-17047, P30DK017047)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- neuropeptide Y, cholecystokinin, corticotropin-releasing factor, hypothalamic arcuate nucleus, hypothalamic paraventricular nucleus, dietary intake, streptozotocin-induced diabetes, neuropeptide gene expression, weight loss
- MeSH terms
- Animals, Base Sequence, Brain, Cholecystokinin, Corticotropin-Releasing Hormone, Diabetes Mellitus, Experimental, Hyperphagia, Hypothalamus, Insulin, Male, Molecular Sequence Data, Neuropeptide Y, Neuropeptides, RNA, Messenger, Gene Expression, Rats, Wistar, In Situ Hybridization, Rats
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