Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice
Abstract
Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.
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Glucocorticoids increase plasma leptin and ghrelin levels, while ghrelin, which also increases with stress, appears to contribute to regulating anxiety and mood.
“Glucocorticoids increase plasma leptin and ghrelin levels, while ghrelin which also increases with stress, appears to contribute to regulating anxiety and mood”
From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Schwartz et al., 1996
Leptin administration to leptin-deficient mice or humans ameliorates hyperglycemia and hyperinsulinemia even when differences in food intake are controlled by pair-feeding.
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From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [158]
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BackgroundSelf-citationLeptin selectively decreases visceral adiposity and enhances insulin action
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“Since administration of exogeneous leptin to ob/ob mice markedly improved the associated diabetic state and decreased the plasma insulin concentrations (5, 22), we next examined whether leptin improved the in vivo actions of insulin.”
BackgroundCentral melanocortin receptors regulate insulin action
Obici, S., Feng, Z., Tan, J., Liu, L., Karkanias, G. B., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12954 · Cited by 370 · see citing works
Metabolic 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-citationFeeding and body-weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin
Inui, A. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(98)01292-2 · Cited by 318 · see citing works
Scacchi, M., Pincelli, A. I., & Cavagnini, F. (1999) · International Journal of Obesity · doi:10.1038/sj.ijo.0800807 · Cited by 316 · see citing works
Short Term Effects of Leptin on Hepatic Gluconeogenesis and in Vivo Insulin Action
Rossetti, L., Massillon, D., Barzilai, N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., & Wang, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.27758 · Cited by 304 · see citing works
A Leptin Dose-Response Study in Obese (ob/ob) and Lean (+/?) Mice
Harris, R. B. S., Zhou, J. F., Redmann, S. M., Smagin, G. N., Smith, S. R., Rodgers, E. V., & Zachwieja, J. J. (1998) · Endocrinology · doi:10.1210/endo.139.1.5675 · Cited by 311 · see citing works
Hypothalamic 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
“In contrast, leptin inhibits the transcription of Npy and Agrp genes in the hypothalamus (Stephens et al. 1995, Schwartz et al. 1996, Mizuno & Mobbs 1999).”
BackgroundKulkarni, R. N., Wang, Z. L., Wang, R. M., Hurley, J. D., Smith, D. M., Ghatei, M. A., Withers, D. J., Gardiner, J. V., Bailey, C. J., & Bloom, S. R. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119818 · Cited by 296 · see citing works
“The results shown in our study relate to acute changes in insulin levels observed within minutes of leptin injection and are not inconsistent with earlier reports (4, 5, 30, 46).”
BackgroundResultThe Stimulatory Effect of Leptin on the Neuroendocrine Reproductive Axis of the Monkey 1
Finn, P. D., Cunningham, M. J., Pau, K. ‐. F., Spies, H. G., Clifton, D. K., & Steiner, R. A. (1998) · Endocrinology · doi:10.1210/endo.139.11.6297 · Cited by 294 · see citing works
Leptin revisited: its mechanism of action and potential for treating diabetes
Coppari, R., & Bjørbæk, C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3757 · Cited by 295 · see citing works
Morton, G. J., Gelling, R. W., Niswender, K. D., Morrison, C. D., Rhodes, C. J., & Schwartz, M. W. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.10.009 · Cited by 292 · see citing works
Self-citationDynamics of Gut-Brain Communication Underlying Hunger
Beutler, L. R., Chen, Y., Ahn, J. S., Lin, Y.-C., Essner, R. A., & Knight, Z. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.043 · Cited by 286 · see citing works
“, 2004) and neurotransmitter levels (Schwartz et al., 1996; Stephens et al., 1995).”
BackgroundThe Molecular Genetics of Rodent Single Gene Obesities
Leibel, R. L., Chung, W. K., & Chua, S. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.51.31937 · Cited by 277 · see citing works
Leptin in human physiology and therapeutics
Dardeno, T. A., Chou, S. H.-H., Moon, H., Chamberland, J. P., Fiorenza, C. G., & Mantzoros, C. S. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.06.002 · Cited by 288 · see citing works
“After being injected with leptin, ob/ob mice exhibited significantly greater reductions in serum glucose levels as compared to pair-fed ob/ ob controls, even before any significant reduction in body weight [204].”
Neuropeptide 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
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
Hedbacker, K., Birsoy, K., Wysocki, R. W., Asilmaz, E., Ahima, R. S., Farooqi, I. S., & Friedman, J. M. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2009.11.007 · Cited by 280 · see citing works
Neuropeptide Y in normal eating and in genetic and dietary-induced obesity
Beck, B. (2006) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2006.1855 · Cited by 281 · see citing works
Wang, H., Storlien, L. H., & Huang, X. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00230.2001 · Cited by 280 · see citing works
“Conversely, overexpression of Arc NPY mRNA has been reported in mice that lack leptin (ob/ob) and in leptin receptor-deficient db/db mice (14, 18).”
BackgroundHighman, T. J., Friedman, J. E., Huston, L. P., Wong, W. W., & Catalano, P. M. (1998) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(98)70540-x · Cited by 272 · see citing works
Jaquet, D., Léger, J., Lévy‐Marchal, C., Oury, J., & Czernichow, P. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.4.4731 · Cited by 275 · see citing works
Reduced central leptin sensitivity in rats with diet-induced obesity
Levin, B. E., & Dunn-Meynell, A. A. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00245.2002 · Cited by 264 · see citing works
“Leptin normally inhibits ARC NPY expression (26, 28).”
BackgroundInfluentialRegulation of leptin production: sympathetic nervous system interactions
Rayner, D. V., & Trayhurn, P. (2001) · Journal of Molecular Medicine · doi:10.1007/s001090100198 · Cited by 250 · see citing works
Leptin: physiology and pathophysiology
Frühbeck, G., Jebb, S. A., & Prentice, A. M. (1998) · Clinical Physiology · doi:10.1046/j.1365-2281.1998.00129.x · Cited by 254 · see citing works
ADIPOCYTE DIFFERENTIATION AND LEPTIN EXPRESSION
Hwang, C.-S., Loftus, T. M., Mandrup, S., & Lane, M. D. (1997) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.13.1.231 · Cited by 247 · see citing works
Relatively low plasma leptin concentrations precede weight gain in Pima Indians
Ravussin, É., Pratley, R. E., Maffei, M., Wang, H., Friedman, J. M., Bennett, P. H., & Bogardus, C. (1997) · Nature Medicine · doi:10.1038/nm0297-238 · Cited by 240 · see citing works
Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism
Pereira, S., Cline, D. L., Glavas, M. M., Covey, S. D., & Kieffer, T. J. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa027 · Cited by 247 · see citing works
Kim, Y., Uotani, S., Pierroz, D. D., Flier, J. S., & Kahn, B. B. (2000) · Endocrinology · doi:10.1210/endo.141.7.7536 · Cited by 245 · see citing works
Routh, V. H. (2002) · Physiology & Behavior · doi:10.1016/s0031-9384(02)00761-8 · Cited by 237 · see citing works
- Authors
- Schwartz, M. W., Baskin, D. G., Bukowski, T. R., Kuijper, J. L., Foster, D., Lasser, G., Prunkard, D. E., Porte, D., Woods, S. C., Seeley, R. J., & Weigle, D. S.
- Affiliations
- Departments of Medicine Seattle, Washington
- Biological Structure, and Psychology Seattle, Washington
- Seagen (Canada) (CA)
- University of Washington (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1996-04-01
- Volume
- 45
- Issue
- 4
- Pages
- 531-535
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2154555913
- Semantic Scholar
- c410a5e2a945c2b99b27f91a7924c39febf099ae
- Cited by
- 904
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 14 · 2020: 11 · 2019: 12 · 2018: 13 · 2017: 18 · 2016: 26 · 2015: 22 · 2014: 33 · 2013: 28 · 2012: 23
- FWCI
- 25.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, DK17844, DK-17047, R01DK012829, P30DK017047)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, ob/ob mice, neuropeptide Y, hypothalamus, arcuate nucleus, hyperglycemia, insulin, obesity, db/db mice, corticotropin-releasing factor, paraventricular nucleus, dietary intake, body weight, leptin resistance, pair feeding, glucose homeostasis, insulin resistance
- MeSH terms
- Insulin Secretion, Animals, Arcuate Nucleus of Hypothalamus, Blood Glucose, Cerebral Cortex, Corticotropin-Releasing Hormone, Cricetinae, Hippocampus, Hypothalamus, Insulin, Kidney, Mice, Inbred C57BL, Mice, Obese, Neuropeptide Y, Obesity, Proteins, Recombinant Proteins, RNA, Messenger, Transfection, Gene Expression, In Situ Hybridization, Leptin, Mice
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