Cited by 389Regulation of Appetite and ObesityNeuropeptides and Animal PhysiologyHypothalamic control of reproductive hormones

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Effect of Intracerebroventricular Insulin Infusion on Diabetic Hyperphagia and Hypothalamic Neuropeptide Gene Expression

Sipols, Alfred J, Baskin, Denis G, Schwartz, Michael W·1995·Diabetes

DOI 10.2337/diab.44.2.147

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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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“Previous studies have shown that POMC neurons in the arcuate nucleus of the hypothalamus play an important role in regulating metabolism (Schwartz et al., 1992; Sipols et al., 1995; Hill et al., 2010; Zeltser et al., 2012).”
Result
Insulin regulates GLUT4 in the ventromedial hypothalamus to restore the sympathoadrenal response to hypoglycemia in diabetic rats
Agrawal, R., Vieira‐de‐Abreu, A., DURUPT, G. T., Taylor, C., Chan, O. T. M., & Fisher, S. J. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00324.2018 · Cited by 5
“Systemic insulin deficiency in STZ-diabetic rats is associated with reduced brain insulin levels (39).”
Background
Insulin is not a prerequisite for rapid regulation of neuropeptide Y gene transcription in the arcuate nucleus in food-restricted rats
Goto, M., Arima, H., Hiroi, M., Shimizu, H., Watanabe, M., Hayashi, M., Banno, R., Sato, I., Ozaki, N., Nagasaki, H., et al. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.04.008 · Cited by 5
Impaired activation of celiac ganglion neurons in vivo after damage to their sympathetic nerve terminals
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“To demonstrate that ganglionic Fos responses to intraperitoneal 2-DG were due to central glucopenia and resultant activation of preganglionic nerves of the celiac ganglia, two groups of rats were given injections into the third cerebral ventricle via chronic catheter (Sipols et al., 1995).”
Method
Diabetic Hyperphagia—Ghrelin in the Driver’s Seat
Gelling, R. W. (2006) · Endocrinology · doi:10.1210/en.2006-0294 · Cited by 5
Regulation of Food Intake and Body Weight
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Self-citation
Peripheral influences on central melanocortin neurons
Murphy, K. G., & Bloom, S. R. (2005) · Peptides · doi:10.1016/j.peptides.2004.12.027 · Cited by 5
Hypothalamic Origin of Prevalent Human Disease
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Regulación de la ingesta alimentaria: una perspectiva clínica
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Tamayo-Molina, Y. S., Giraldo, M. A., Rodríguez, B. A., & Machado, G. (2024) · Scientific Reports · doi:10.1038/s41598-024-77915-4 · Cited by 6
Fam163a knockdown and mitochondrial stress in the arcuate nucleus of hypothalamus reduce AgRP neuron activity and differentially regulate mitochondrial dynamics in mice
Erdogan, C. S., Yavuz, Y., Özgün, H. B., Bilgin, V. A., Ağuş, S., Kalkan, U. F., & Yılmaz, B. (2025) · Acta Physiologica · doi:10.1111/apha.70020 · Cited by 3
Applied physiology: the control of weight
English, P., & Wilding, J. P. H. (2002) · Current Paediatrics · doi:10.1054/cupe.2001.0264 · Cited by 3
Increased production of active ghrelin is relevant to hyperphagia in nonobese spontaneously diabetic Torii rats
Mifune, H., Nishi, Y., Tajiri, Y., et al. (2011) · Metabolism · doi:10.1016/j.metabol.2011.09.001 · Cited by 3
“The hyperphagia observed in SDT rats appears to arise, at least in part, from deficient hypothalamic signaling by insulin and leptin, which in turn leads to the activation of neuropeptide Y/AgRP (agouti-related protein) neurons [9,16] separate from the participation of the ghrelin production.”
Background
Growth Hormone, Insulin, and Insulin-like Growth Factor-I: Do They Interact at the Blood-Brain Barrier?
Pan, W., Yu, Y., Nyberg, F., et al. (2006) · Elsevier eBooks · doi:10.1016/b978-012088484-1/50009-4 · Cited by 3
Role of cholecystokinin in the reduction of endomorphin-2-induced antinociception in diabetic mice
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Background
The hypothalamus and energy balance
Benedini, S. (2009) · Sport Sciences for Health · doi:10.1007/s11332-009-0079-5 · Cited by 3
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Background
Effect of Permanent Hypoinsulinemia on Appetite, Performance, Carcass Composition, Blood Metabolites and Leptin Concentrations in Lambs
Moslemipur, F., Torbatinejad, N. M., Khazali, H., Hassani, S., & Ghoorchi, T. (2009) · Asian-Australasian Journal of Animal Sciences · doi:10.5713/ajas.2009.80626 · Cited by 3
“Secretion and release of two potent orexigenic peptides, NPY and AgRP, are inhibited by insulin (Sipols et al., 1995; Saho et al., 1997; Henry et al., 1999; Sorensen et al., 2002; Breen et al., 2005), while α-MSH secretion is induced (Benoit et al., 2002; Sorensen et al., 2002; Breen et al., 2005).”
Background
Hormonal mediation of energy homeostasis in obesity, diabetes and related disorders
Woods, S. C., & Seeley, R. J. (2005) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2005.08.004 · Cited by 3
Attenuation of somatodendritic responses to 8-hydroxy-2-di-npropylamino tetralin following long-term dietary sugar consumption in rats.
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How appetite is controlled
Wren, A., & Bloom, S. R. (2002) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/00060793-200204000-00004 · Cited by 3
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Machado, M. V., & Ulate-Montero, G. (2010) · Acta Médica Costarricense · Cited by 3
Insulin
Grayson, B. E., & Woods, S. C. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-385095-9.00151-2 · Cited by 3

Authors: Sipols, A. J., Baskin, D. G., & Schwartz, M. W.
Affiliations: University of Washington (US)
ORCID: Baskin, Denis G
Schwartz, Michael W
Venue: Diabetes
Publisher: American Diabetes Association
Published: 1995-02-01
Volume: 44
Issue: 2
Pages: 147-151
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diab.44.2.147
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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Effect of Intracerebroventricular Insulin Infusion on Diabetic Hyperphagia and Hypothalamic Neuropeptide Gene Expression

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