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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Deficiency of leptin or insulin, or of their receptors in the CNS, results in hyperphagia, weight gain, and insulin resistance.
“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]
icv infusion of insulin at a dose that attenuates diabetic hyperphagia fails to normalize blood glucose levels in STZ-diabetic rats.
“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]
Cited by
Sorted by citations
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 · see citing works
Self-citationIdentification of targets of leptin action in rat hypothalamus.
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P., & Baskin, D. G. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118891 · Cited by 1,475 · see citing works
“NPY genes, as described elsewhere (16, 25).”
Self-citationSignals That Regulate Food Intake and Energy Homeostasis
Woods, S. C., Seeley, R. J., Porte, D., & Schwartz, M. W. (1998) · Science · doi:10.1126/science.280.5368.1378 · Cited by 1,169 · see citing works
Self-citationHypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904 · see citing works
“These 'central' effects of insulin include modulation of feeding behavio”
BackgroundNeurobiology of food intake in health and disease
Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3745 · Cited by 748 · see citing works
Self-citationDecreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719 · see citing works
“and their central administration decreases food intak”
Self-citationInsulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.004 · Cited by 695 · see citing works
The role of insulin receptor signaling in the brain
Plum, L., Schubert, M., & Brüning, J. C. (2005) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2005.01.008 · Cited by 604 · see citing works
Havel, P. J. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122601102 · Cited by 476 · see citing works
Role of neuropeptides in appetite regulation and obesity – A review
Arora, S., & Anubhuti, A. (2006) · Neuropeptides · doi:10.1016/j.npep.2006.07.001 · Cited by 451 · see citing works
“Furthermore, POMC mRNA is reduced by 80% in rats with untreated diabetes, and this can be attenuated by peripheral insulin treatment which partially reduces the hyperglycemia (Sipols et al., 1995).”
BackgroundCentral insulin action in energy and glucose homeostasis
Plum, L. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29063 · Cited by 438 · see citing works
Niswender, K. D., & Schwartz, M. W. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/s0091-3022(02)00105-x · Cited by 421 · see citing works
Self-citationBaskin, D. G., Lattemann, D. F., Seeley, R. J., Woods, S. C., Porte, D., & Schwartz, M. W. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01974-5 · Cited by 398 · see citing works
Self-citationHormonal regulation of food intake
Stanley, S., Wynne, K., McGowan, B., & Bloom, S. (2005) · Physiological Reviews · doi:10.1152/physrev.00015.2004 · Cited by 372 · see citing works
“Furthermore, POMC expression is greatly reduced in rats with untreated diabetes and partly restored by peripheral insulin treatment (371).”
BackgroundLeptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“Administration of either peptide into the brain reduces food intake and body weight (30, 76, 200), while conversely, deficiency of either hormone or their respective receptors in the CNS results in hyperphagia, weight gain, and insulin resistance (27, 174, 183, 212).”
BackgroundSelf-citationInsulin Signaling in the Central Nervous System
Porte, D., Baskin, D. G., & Schwartz, M. W. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1264 · Cited by 336 · see citing works
Self-citationFood Intake and the Regulation of Body Weight
Woods, S. C., Schwartz, M. W., Baskin, D. G., & Seeley, R. J. (2000) · Annual Review of Psychology · doi:10.1146/annurev.psych.51.1.255 · Cited by 332 · see citing works
“The importance of insulin as an adiposity signal to the brain is revealed by the observation that insulin-deficient animals are hyperphagic and that the administration of small amounts of insulin locally into the brain of such animals eliminates their hyperphagia (Sipols et al 1995).”
BackgroundSelf-citationPlum, L. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27123 · Cited by 326 · see citing works
“Furthermore, icv injection of insulin and leptin results in reduced expression of NPY and AgRP and increased expression of POMC (18, 19).”
BackgroundMetabolic effects of obesity: A review
Singla, P. (2010) · World Journal of Diabetes · doi:10.4239/wjd.v1.i3.76 · Cited by 330 · see citing works
Model for the regulation of energy balance and adiposity by the central nervous system
Schwartz, M. W., Baskin, D. G., Kaiyala, K. J., & Woods, S. C. (1999) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/69.4.584 · Cited by 323 · see citing works
Self-citationHypothalamic and brainstem neuronal circuits controlling homeostatic energy balance.
Schneeberger, M., Gomis, R., & Claret, M. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0398 · Cited by 301 · see citing works
“…DOI: 10.1530/JOE-13-0398 2014 Society for Endocrinology Printed in Great Britain IR signaling pathway results in reduced expression of NPY and increased levels of POMC in the ARC, thus stimulating an anorexigenic effect (Schwartz et al. 1992, Sipols et al. 1995, Benoit et al. 2002).”
BackgroundInfluentialAugmentation of drug reward by chronic food restriction
Carr, K. D. (2002) · Physiology & Behavior · doi:10.1016/s0031-9384(02)00759-x · Cited by 300 · see citing works
Cox, D. J., Kovatchev, B. P., Gonder-Frederick, L. A., Summers, K. H., McCall, A. L., Grimm, K. J., & Clarke, W. L. (2005) · Diabetes Care · doi:10.2337/diacare.28.1.71 · Cited by 299 · see citing works
“Complex effects on peptide neurotransmitters may be produced by uncontrolled diabetes (10,11).”
BackgroundBenedict, C., Kern, W., Schultes, B., Born, J., & Hallschmid, M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2606 · Cited by 296 · see citing works
“It is also possible that intranasal insulin suppresses food intake by inhibiting the expression of neuropeptide Y (24) as well as by stimulating the production of melanocortins (25).”
BackgroundThe role of dopamine in motivation for food in humans: implications for obesity
Wang, G.-J., Volkow, N. D., & Fowler, J. S. (2002) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.6.5.601 · Cited by 285 · see citing works
“These adiposity signals stimulate a catabolic pathway [21,22] and inhibit an anabolic pathway [23-25] that originate in the arcuate nucleus.”
BackgroundNeuropeptide Y: the universal soldier
Pedrazzini, T., Pralong, F. P., & Grouzmann, E. (2003) · Cellular and Molecular Life Sciences · doi:10.1007/s000180300029 · Cited by 286 · see citing works
Pancreatic signals controlling food intake; insulin, glucagon and amylin
Woods, S. C., Lutz, T. A., Geary, N., & Langhans, W. (2006) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2006.1858 · Cited by 286 · see citing works
“When insulin is administered locally into the brain of animals lacking insulin, their hyperphagia is attenuated with no change in other diabetic symptoms (Sipols et al. 1995).”
Neuroendocrine Responses to Starvation and Weight Loss
Schwartz, M. W., & Seeley, R. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199706193362507 · Cited by 265 · see citing works
Self-citationInsulin and Leptin as Adiposity Signals
Benoit, S. C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.267 · Cited by 266 · see citing works
“Administration of insulin into the i3vt of the brain also causes increased expression of corticotropin (ACTH)-releasing hormone mRNA in the PVN ( Sipols et al., 1995; Schwartz et al., 1996b).”
BackgroundGut hormones in the control of appetite
Murphy, K. G., & Bloom, S. R. (2004) · Experimental Physiology · doi:10.1113/expphysiol.2004.027789 · Cited by 253 · see citing works
“Though this effect may be secondary to the absence of the peripheral effects of insulin, it is interesting to note that CNS insulin replacement to type 1 diabetic rats alleviates their hyperphagia, suggesting that insulin may have a direct anorectic effect (Sipols et al. 1995).”
BackgroundInsulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis
Niswender, K. D., Baskin, D. G., & Schwartz, M. W. (2004) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2004.07.009 · Cited by 250 · see citing works
Self-citationHypothalamic control of energy balance: different peptides, different functions
LEIBOWITZ, S. F., & Wortley, K. E. (2004) · Peptides · doi:10.1016/j.peptides.2004.02.006 · Cited by 235 · see citing works
“In diabetic rats, CRF expression in the PVN is increased, perhaps related to the activation of the HPA axis, and this effect is generally unaffected or further enhanced by the administration of insulin [67,68,335,377] .”
Brain Insulin: Regulation, Mechanisms of Action and Functions
Gerozissis, K. (2003) · Cellular and Molecular Neurobiology · doi:10.1023/a:1022598900246 · Cited by 235 · see citing works
“…of NPY in arcuate nucleus neurons is decreased after systemic or central administration of insulin and leptin whereas NPY neurons become overactive when the levels of these hormones fall during undernutrition (Air et al., 2002; Schwartz et al., 1992a; Sipols et al., 1995; Williams et al., 2001).”
BackgroundEffect of LPS on the permeability of the blood–brain barrier to insulin
Xaio, H., Banks, W. A., Niehoff, M. L., & Morley, J. E. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03247-9 · Cited by 231 · see citing works
Leptin and Insulin Action in the Central Nervous System
Porte, D., Baskin, D. G., & Schwartz, M. W. (2002) · Nutrition Reviews · doi:10.1301/002966402320634797 · Cited by 229 · see citing works
“decrease can be attenuated by systemic insulin treatment with a dose that partly reversed the hyperglycemia.(33)”
BackgroundSelf-citationAdiposity signals and food reward: expanding the CNS roles of insulin and leptin
Figlewicz, D. P. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00602.2002 · Cited by 221 · see citing works
“Insulin and leptin decrease the expression of hypothalamic NPY (11, 107, 113, 125), and these observations have led to an extensive investigation of the medial hypothalamus as a target region for insulin and leptin effects on body weight regulation.”
BackgroundThe endocrinology of food intake
Begg, D. P., & Woods, S. C. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.136 · Cited by 199 · see citing works
Insulin, leptin, and food reward: update 2008
Figlewicz, D. P., & Benoit, S. C. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90725.2008 · Cited by 202 · see citing works
“Among the most extensively studied mediators are neuropeptide Y (42, 43, 166, 173, 188), proopiomelanocortin (POMC) and its product -melanocyte-stimulating hormone, and the melanocortin antagonist agouti-related peptide (AgRP) (for reviews see Refs.”
BackgroundHavel, P. J., Uriu-Hare, J. Y., Liu, T., Stanhope, K. L., Stern, J. S., Keen, C. L., & Ahrén, B. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.274.5.r1482 · Cited by 198 · see citing works
“In one study, these investigators demonstrated that administration of insulin into the third ventricle of STZ diabetic rats at doses that did not alter peripheral insulinemia or plasma glucose levels inhibited the diabetic hyperphagia by ,50% and decreased, but did not normalize, the overexpression of neuropeptide Y (…”
BackgroundThe role of NPY in hypothalamic mediated food intake
Mercer, R. E., Chee, M. J. S., & Colmers, W. F. (2011) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2011.06.001 · Cited by 194 · see citing works
Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies
Gerozissis, K. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.050 · Cited by 197 · see citing works
“Absolute insulin deficiency is accompanied by pronounced “diabetic hyperphagia” (Sipols et al., 1995) and defective insulin signalling is a major element linking obesity and diabetes (Lin et al.”
BackgroundObesity, diabetes and the central nervous system
Porte Jr., D., Seeley, R. J., Woods, S. C., Baskin, D. G., Figlewicz, D. P., & Schwartz, M. W. (1998) · Diabetologia · doi:10.1007/s001250051002 · Cited by 186 · see citing works
“As expected, the effect of food deprivation and insulin-deficient diabetes to stimulate food intake are both reversed by insulin treatment [74, 215] and associated with increased NPY, and reduced expression of mRNA for CRH in D.”
BackgroundMethodInfluentialSelf-citationMizuno, T. M., Makimura, H., Silverstein, J. H., Roberts, J. L., Lopingco, T., & Mobbs, C. V. (1999) · Endocrinology · doi:10.1210/endo.140.10.6966 · Cited by 189 · see citing works
Signalling from the periphery to the brain that regulates energy homeostasis
Kim, K., Seeley, R. J., & Sandoval, D. A. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2018.8 · Cited by 183 · see citing works
Effect of restraint stress on food intake and body weight is determined by time of day
Rybkin, I. I., Zhou, Y., Vólaufová, J., Smagin, G. N., Ryan, D. H., & Harris, R. B. S. (1997) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1997.273.5.r1612 · Cited by 182 · see citing works
AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity.
Vohra, M. S., Benchoula, K., Serpell, C., & Hwa, W. E. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174611 · Cited by 153 · see citing works
Sugimoto, K., Murakawa, Y., & Sima, A. A. F. (2000) · Diabetes/Metabolism Research and Reviews · doi:10.1002/1520-7560(200011/12)16:6
Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood
Lee, S.-H., Zabolotny, J. M., Huang, H., Lee, H., & Kim, Y.-B. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.011 · Cited by 176 · see citing works
“Insulin decreases expression of orexigenic AgRP and NPY, leading to decreased food intake [44].”
BackgroundInsulin controls food intake and energy balance via NPY neurons
Loh, K., Zhang, L., Brandon, A. E., Wang, Q., Begg, D. P., Qi, Y., Fu, M., Kulkarni, R. N., Teo, J. D., Baldock, P. A. J., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.03.013 · Cited by 173 · see citing works
“The ability of insulin to regulate NPY expression is supported by several early studies showing that acute elevation of insulin levels by direct administration into the brain was able to reduce ARC NPY levels [12,13].”
BackgroundBrain regulation of energy balance and body weight
Rui, L. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9261-9 · Cited by 168 · see citing works
STRUBBE, J. H., & Woods, S. C. (2004) · Psychological Review · doi:10.1037/0033-295x.111.1.128 · Cited by 171 · see citing works
Air, E. L., Strowski, M. Z., Benoit, S. C., Conarello, S., Salituro, G., Guan, X.-M., Liu, K., Woods, S. C., & Zhang, B. B. (2002) · Nature Medicine · doi:10.1038/nm0202-179 · Cited by 169 · see citing works
German, J. P., Thaler, J. P., Wisse, B. E., Oh-I, S., Sarruf, D. A., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J. (2011) · Endocrinology · doi:10.1210/en.2010-0890 · Cited by 169 · see citing works
“blood glucose levels in STZ-diabetic rats (36),”
Self-citationLaugero, K. D., Falcón, L. M., & Tucker, K. L. (2010) · Appetite · doi:10.1016/j.appet.2010.11.001 · Cited by 163 · see citing works
Neuropeptide Signaling in the Integration of Metabolism and Reproduction
Crown, A., Clifton, D. K., & Steiner, R. A. (2007) · Neuroendocrinology · doi:10.1159/000109095 · Cited by 165 · see citing works
Baldock, P. A., Lee, N. J., Driessler, F., Lin, S., Allison, S., Stehrer, B., Lin, E.-J. D., Zhang, L., Enriquez, R. F., Wong, I. P. L., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008415 · Cited by 164 · see citing works
“We propose that in situations where hypothalamic NPY expression is decreased, as in short-term overfeeding in which serum leptin levels rise and in turn reduces central NPY signaling [12,15], bone formation is stimulated as was the case in NPY 2/2 mice.”
BackgroundEarly Life Origins of Obesity: Role of Hypothalamic Programming
Bouret, S. G. (2009) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e3181977375 · Cited by 160 · see citing works
“injections of small amounts of insulin into the brain of insulin-deficient animals can eliminate hyperphagia (8).”
BackgroundCentral mechanisms involved in the orexigenic actions of ghrelin
Andrews, Z. B. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.014 · Cited by 158 · see citing works
McMinn, J. E., Wilkinson, C. W., Havel, P. J., Woods, S. C., & Schwartz, M. W. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.2.r695 · Cited by 156 · see citing works
Self-citationGender Differences in the Control of Energy Homeostasis
Woods, S. C., Gotoh, K., & Clegg, D. J. (2003) · Experimental Biology and Medicine · doi:10.1177/153537020322801012 · Cited by 144 · see citing works
Neuropeptide Y, α-melanocyte–stimulating hormone, and monoamines in food intake regulation
Ramos, E. J. B., Meguid, M. M., Campos, A. C. L., & Coelho, J. C. U. (2005) · Nutrition · doi:10.1016/j.nut.2004.06.021 · Cited by 142 · see citing works
Physiology and gene regulation of the brain NPY Y1 receptor
Eva, C. E., Serra, M., Mele, P., Panzica, G., & Oberto, A. (2006) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2006.07.002 · Cited by 139 · see citing works
“Similarly, the expression of NPY in rat ARC neurons decreased after the central administration of insulin, whereas ARC NPY neurons become overactive when the levels of this hormone fall during undernutrition [322,338,351].”
BackgroundPlum, L., Rother, E., Münzberg, H., Wunderlich, F. T., Morgan, D. A., Hampel, B., Shanabrough, M., Janoschek, R., Könner, A. C., Alber, J., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.012 · Cited by 138 · see citing works
Protein tyrosine phosphatase-1B in diabetes
Kennedy, B. P., & Ramachandran, C. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(00)00305-1 · Cited by 132 · see citing works
Cerebral glucose metabolism in diabetes mellitus
McCall, A. L. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.052 · Cited by 131 · see citing works
Leptin Deficiency Induced by Fasting Impairs the Satiety Response to Cholecystokinin
McMinn, J. E., Sindelar, D. K., Havel, P. J., & Schwartz, M. W. (2000) · Endocrinology · doi:10.1210/endo.141.12.7815 · Cited by 129 · see citing works
Self-citationCentral leptin increases insulin sensitivity in streptozotocin-induced diabetic rats
Lin, C.-Y., Higginbotham, D. A., Judd, R. L., & White, B. D. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00489.2001 · Cited by 124 · see citing works
“Diabetic hyperphagia is suppressed by administration of insulin directly into the brain (35) or by subcutaneous insulin implant (17).”
BackgroundResultMetabolic Status Regulates Ghrelin Function on Energy Homeostasis
Briggs, D. I., & Andrews, Z. B. (2010) · Neuroendocrinology · doi:10.1159/000322589 · Cited by 123 · see citing works
“Fourthly, DIO suppresses the basal AMPK activity in the hypothalamus, although this suppression is only significant in the PVN [”
BackgroundHong, S.-H., Lee, K., Kwak, S., Kim, A., Bai, H., Jung, M., Kwon, O., Song, W., Tatar, M., & Yu, K. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002857 · Cited by 123 · see citing works
“while inhibiting insulin receptors of the hypothalamic ARC nucleus causes hyperphasia and obesity in rodent models [39,40].”
Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators
Sánchez-Lasheras, C., Könner, A. C., & Brüning, J. C. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.08.002 · Cited by 120 · see citing works
“decrease NPY and AgRP mRNA levels [18,93,168,176].”
BackgroundAnderwald, C. H., Brabant, G. E., Bernroider, E., Horn, R., Brehm, A., Waldhäusl, W. K., & Roden, M. (2003) · Diabetes · doi:10.2337/diabetes.52.7.1792 · Cited by 120 · see citing works
“Likewise, insulin also reduces NPY expression in the CNS as demonstrated by intracerebroventricular insulin infusion in diabetic rats (32).”
BackgroundInsulin-associated weight gain in obese type 2 diabetes mellitus patients: What can be done?
Brown, A., Guess, N., Dornhorst, A., Taheri, S., & Frost, G. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13009 · Cited by 113 · see citing works
Energy regulatory signals and food reward
Figlewicz, D. P., & Sipols, A. J. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.03.002 · Cited by 111 · see citing works
“Among the most extensively studied CNS mediators are NPY (Clark et al., 1984; Schwartz et al., 1992; Sipols et al., 1995; White et al., 1990), POMC and its product α-melanocyte stimulating hormone (α-MSH), and the melanocortin antagonist, AgRP (for reviews, see: Benoit et al., 2000; Morton and…”
BackgroundSelf-citationThe Melanocortin Melanocyte-Stimulating Hormone/Adrenocorticotropin4–10Decreases Body Fat in Humans1
Fehm, H. L., Smolnik, R., Kern, W., McGregor, G. P., Bickel, U., & Jan Born, A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7298 · Cited by 113 · see citing works
Warne, J. P. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.09.036 · Cited by 112 · see citing works
Hypothalamic leptin regulation of energy homeostasis and glucose metabolism
Morton, G. J. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.135590 · Cited by 111 · see citing works
“Central administration of either hormone reduces food intake and body weight (Woods et al. 1979; Campfield et al. 1995) while conversely, deficiency of either hormone results in hyperphagia (Zhang et al. 1994; Sipols et al. 1995).”
BackgroundBrain insulin and feeding: a bi-directional communication
Gerozissis, K. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.044 · Cited by 108 · see citing works
Adiposity signals, genetic and body weight regulation in humans
Cancello, R., Tounian, A., Poitou, C., & Clément, K. (2004) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70112-x · Cited by 107 · see citing works
“Type 1 diabetic patients with a deficit of insulin secretion show pronounced hyperphagia known as “diabetic hyperphagia” and in streptozotocin-induced diabetic rats infusion of a low dose of insulin (6 days) reduced food intake by 58% and body weight by 69% [22].”
BackgroundNamKoong, C., Kim, M., Jang, P., Han, S. M., Park, H. S., Koh, E. H., Lee, W. J., Kim, J. Y., Park, I. S., Park, J. Y., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.1.63 · Cited by 106 · see citing works
The floating blueprint of hypothalamic feeding circuits
Horváth, T. L., & Diano, S. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1479 · Cited by 102 · see citing works
Neuroendocrine mechanisms regulating food intake and body weight
McMinn, J. E., Baskin, D. G., & Schwartz, M. W. (2000) · Obesity Reviews · doi:10.1046/j.1467-789x.2000.00007.x · Cited by 97 · see citing works
“In addition, intracerebroventricular injections of insulin into the brain reduce food intake and body weight in rodents without causing malaise (13), hyperinsulinaemia or hypoglycaemia (14).”
BackgroundSelf-citationSTRUBBE, J. H., & van Dijk, G. (2002) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(02)00016-7 · Cited by 100 · see citing works
“However, the fact that insulin replacement therapy in the central nervous system of type-I diabetic rats is partly able to reverse the hyperphagia in these animals suggests that insulin action on food intake is independent of leptin [66].”
BackgroundNew model for the regulation of energy balance and adiposity by the central nervous system
Kaiyala, K., Woods, S. C., & Schwartz, M. (1995) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/62.5.1123s · Cited by 98 · see citing works
Self-citationInsulin Inhibits Neuropeptide Y Gene Expression in the Arcuate Nucleus through GABAergic Systems
Sato, I., Arima, H., Ozaki, N., Watanabe, M., Goto, M., Hayashi, M., Banno, R., Nagasaki, H., & Oiso, Y. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2739-05.2005 · Cited by 98 · see citing works
“…(1) insulin receptors are expressed in the arcuate nucleus, and central injection of insulin decreases NPY gene expression (Marks et al., 1990; Sipols et al., 1995; Benoit et al., 2002); (2) decreases in insulin levels induced by streptozotocin injection or food deprivation lead to increases…”
Obesity: molecular bases of a multifactorial problem
Palou, A., Serra, F. A., Bonet, M. L., & Picó, C. (2000) · European Journal of Nutrition · doi:10.1007/s003940070017 · Cited by 97 · see citing works
Cheng, C. Y. Y., Chu, J. Y. S., & Chow, B. K. C. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.178 · Cited by 98 · see citing works
“…of appetite such as leptin (Cowley et al, 2001; Elmquist et al, 1997; Håkansson et al, 1996; Stephens et al, 1995), insulin (Benoit et al, 2002; Sipols et al, 1995; van Houten et al, 1979), and ghrelin (Hewson and Dickson, 2000; Kamegai et al, 2000; Willesen et al, 1999) act through the MC…”
BackgroundAntiglycating potential of Zingiber officinalis and delay of diabetic cataract in rats.
Saraswat, M., Suryanarayana, P., Reddy, P. Y., Patil, M. A., Balakrishna, N., & Reddy, G. B. (2010) · PubMed Central · Cited by 97 · see citing works
Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis
Chen, W., Balland, É., & Cowley, M. A. (2017) · Neuroendocrinology · doi:10.1159/000455865 · Cited by 99 · see citing works
New Twist on Neuronal Insulin Receptor Signaling in Health, Disease, and Therapeutics
Wada, A., Yokoo, H., Yanagita, T., & Kobayashi, H. (2005) · Journal of Pharmacological Sciences · doi:10.1254/jphs.crj05006x · Cited by 95 · see citing works
The New Biology of Body Weight Regulation
Schwartz, M. W., & Seeley, R. J. (1997) · Journal of the American Dietetic Association · doi:10.1016/s0002-8223(97)00018-7 · Cited by 94 · see citing works
Self-citationDevelopmental programming of hypothalamic neuronal circuits: impact on energy balance control
Ramamoorthy, T. G., Begum, G., Harno, E., & White, A. E. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00126 · Cited by 96 · see citing works
Paranjape, S., & Briski, K. P. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.09.030 · Cited by 92 · see citing works
Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue
Shi, Y., & Baldock, P. A. J. (2011) · Bone · doi:10.1016/j.bone.2011.10.001 · Cited by 90 · see citing works
“Conversely, hypothalamic NPY level is decreased during times of energy excess or after short term overfeeding with increased serum leptin levels [101,102].”
BackgroundGhrelin and lipid metabolism: key partners in energy balance
Varela, L., Vazquez, M. J., Cordido, F., Nogueiras, R., Vidal‐Puig, A., Diéguez, C., & López, M. (2010) · Journal of Molecular Endocrinology · doi:10.1677/jme-10-0068 · Cited by 93 · see citing works
Gut–Brain Axis: Regulation of Glucose Metabolism
Heijboer, A. C., Pijl, H., van den Hoek, A. M., Havekes, L. M., Romijn, J. A., & Corssmit, E. P. M. (2006) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2006.01492.x · Cited by 87 · see citing works
Chan, O. T. M., Chan, S., Inouye, K., Vranić, M., & Matthews, S. G. (2001) · Endocrinology · doi:10.1210/endo.142.11.8474 · Cited by 89 · see citing works
Peripheral tissue–brain interactions in the regulation of food intake
López, M., Tovar, S. A., Vazquez, M. J., Williams, L. M., & Diéguez, C. (2007) · Proceedings of The Nutrition Society · doi:10.1017/s0029665107005368 · Cited by 87 · see citing works
“In the hypothalamus the actions of insulin on food intake and body weight are mediated by NPY (Schwartz et al. 1992b) and the melanocortin system (Sipols et al. 1995; Obici et al. 2001; Benoit et al. 2002).”
BackgroundBenomar, Y., Roy, A.-F., Aubourg, A., Djiane, J., & Taouis, M. (2005) · Biochemical Journal · doi:10.1042/bj20041621 · Cited by 86 · see citing works
Intestinal satiety protein apolipoprotein AIV is synthesized and regulated in rat hypothalamus
Liu, M., Doi, T., Shen, L., et al. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.5.r1382 · Cited by 83 · see citing works
Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance
Wang, B., & Cheng, K. K. Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113552 · Cited by 84 · see citing works
“Insulin-deficient animals are hyperphagia, whereas their voracious appetite could be rectified by central administration of insulin [113,114].”
Background
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
