Cited by 904Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

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Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice

Schwartz, Michael W, Baskin, Denis G, Bukowski, Thomas R, Kuijper, Joseph L, Foster, Donald, Lasser, Gerry, Prunkard, Donna E, Porte, Daniel, Woods, Stephen C, Seeley, Randy J, Weigle, David S·1996·Diabetes

DOI 10.2337/diab.45.4.531

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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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Robberecht, H. J., & Hermans, N. (2016) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2015.0113 · Cited by 38
Plasma Leptin Response to an Epinephrine Infusion in Lean and Obese Women
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Leptin is involved in gender‐related differences in insulin sensitivity
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The role of hypothalamic histamine in leptin-induced suppression of short-term food intake in fasted rats
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Leptin, 20years of searching for glucose homeostasis
Fernández-Formoso, G., Perez‐Sieira, S., González-Touceda, D., Diéguez, C., & Tovar, S. A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.02.008 · Cited by 39
Mammalian adipogenesis regulator (Areg) cells use retinoic acid signalling to be non‐ and anti‐adipogenic in age‐dependent manner
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“In addition, we observed that Aregs, and CD142 (cid:1) ASPCs exposed to “Active” Areg signalling, exhibited, upon exposure to differentiation cocktail, remarkably coherent transcriptional dynamics of a number of genes and pathways that were previously reported to be involved in the RA-mediated inhibition of adipogenes…”
BackgroundMethodInfluential
Leptina: o diálogo entre adipócitos e neurônios
Negrão, A. B., & Licinio, J. (2000) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302000000300004 · Cited by 39
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NPY-induced overfeeding suppresses hypothalamic NPY mRNA expression: potential roles of plasma insulin and leptin
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Self-citation
Adipocyte Versus Pituitary Leptin in the Regulation of Pituitary Hormones: Somatotropes Develop Normally in the Absence of Circulating Leptin
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“Hepatic and gastrocnemius muscle triglycerides were measured by a protocol modified from that of Briaud et al (26) as described previously (21).”
BackgroundMethod
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“ACTIONS IN THE BRAIN Double-labelling experiments have shown colocalization of Ob-Rand NPY-LI in the same arcuate neurons, in agreement with results showing colocalization of Ob-R and NPY at the mRNA level in the arcuate nucleus.19,22 Because NPY is a positive regulator of feeding behaviour, particularly of carbohydra…”
Background
Food intake regulation in rodents: Y5or Y1NPY receptors or both?
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“Central infusion of leptin normalized the abnormal expression of AGRP together with other neuropeptides in ob/ob mice but not in Zucker fa/fa rats or db/db mice (Stephens et al. 1995; Schwartz et al. 1996, 1997; Mizuno et al. 1998; Ebihara et al. 1999).”
Background
Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis
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Self-citation
Leptin Deficiency Per Se Dictates Body Composition and Insulin Action in ob/ob Mice
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Serum Leptin and Weight Gain Over 8 Years in African American and Caucasian Young Adults
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A study in the relationships between leptin, insulin, and body fat in Asian subjects
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Do baseline serum leptin levels predict weight regain after dieting in obese women?
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Metabolic Characterization of a Mouse Deficient in All Known Leptin Receptor Isoforms
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Free fatty acids and insulin levels—relationship to leptin levels and body composition in various patient groups from South Africa
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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)
ORCID: Schwartz, Michael W
Baskin, Denis G
Woods, Stephen C
Seeley, Randy J
Venue: Diabetes
Publisher: American Diabetes Association
Published: 1996-04-01
Volume: 45
Issue: 4
Pages: 531-535
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diab.45.4.531
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 › Endocrinology, Diabetes and Metabolism › 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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Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice

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