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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”
From Role of addiction and stress neurobiology on food intake and obesity (2018) · cites this paper as Schwartz et al., 1996
In the citing paper
“leptin administration to leptin-deficient mice or humans ameliorates hyperglycemia and hyperinsulinemia (60, 141) even when differences of food intake are controlled by pair-feeding (80, 158).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [158]
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BackgroundMelanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes
Gutiérrez-Juárez, R., Obici, S., & Rossetti, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408665200 · Cited by 115
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“The expression of NPY in the arcuate nucleus (ARC) has been shown to clearly increase with food restriction (6, 7) and its levels to be negatively regulated by leptin (8, 9 ). In addition to its role in appetite regulation, NPY subserves other functions and has been implicated in the regulation of LH secretion, partic…”
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“This signal decreases expression of neuropeptides such as agouti-related protein (29) and neuropeptide Y (39, 41), which are orexigenic, and increases expression of other neuropeptides that are anorexigenic, such as proopiomelanocortin (28, 40) and corticotropin-releasing hormone (38).”
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“However, leptin therapy increases insulin sensitivity in the absence of a significant decrease in body weight or causes a greater reduction in blood glucose concentration after leptininduced weight loss than after weight loss induced by pairfeeding alone in wild-type and leptin-deficient rodent models (1,2,16) and imp…”
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“1999), and leptin treatment corrects these metabolic abnormalities via a mechanism that cannot be explained by changes of food intake or body weight (Schwartz et al. 1996; Shimomura et al. 1999).”
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“The ability of leptin administration to reverse metabolic abnormalities in the ob/ob mouse (17, 21, 24) and improve insulin action in normal animals (1, 5, 26) has led to the proposal that leptin may serve as an effective therapy for human obesity.”
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Koch, C. E., Lowe, C., Pretz, D., Steger, J., Williams, L. M., & Tups, A. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12131 · Cited by 111
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“Leptin has been shown to inhibit the expression of neuropeptide Y messenger RNA and protein in rat and mouse hypothalamus (31, 32).”
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CNS Regulation of Glucose Homeostasis
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“Furthermore, leptin-treated ob/ob mice had a 40% reduction in glucose and insulin levels compared with pair-fed ob/ob mice (108).”
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“Insulin and leptin both inhibit feeding and stimulate BAT thermogenesis and may exert these actions partly by inhibiting the ARC NPY neurons that express the OB-Rb leptin receptor mRNA (11, 18, 22, 24, 25).”
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“…from the midregion of the rostrocaudal extent of the arcuate nucleus (which also contains the dorsomedial and ventromedial nuclei), based on our previous experience that NPY mRNA responses to fasting (Marks et al., 1992) and to leptin (Schwartz et al., 1996) are especially robust in this area.”
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“Leptin, a hormone secreted by fat cells, reduces body fat and increases physical activity in rodents (2–4), perhaps by inhibiting the release of neuropeptide Y by the hypothalamus (5, 6).”
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“, 1975; Oltmans, 1983) and neuropeptide Y (Schwartz et al., 1996) activity in the paraventricular nucleus.”
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“Opposite to the actions of leptin in POMC neurons, leptin administration has been shown to inhibit gene transcription of NPY/AgRP in the hypothalamus (Schwartz et al., 1996a, b; Stephens et al., 1995).”
The New Biology of Body Weight Regulation
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Self-citationLeptin: a possible link between food intake, energy expenditure, and reproductive function
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Distribution and Regulation of Galanin-Like Peptide (GALP) in the Hypothalamus of the Mouse
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Cigarette Smoke Exposure Reprograms the Hypothalamic Neuropeptide Y Axis to Promote Weight Loss
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“Under normal physiological conditions, Arc NPY gene expression is negatively regulated by leptin signalling (16, 43) and positively by negative energy balance (9, 44).”
BackgroundMantovani, G., Macciò, A., Madeddu, C., Mura, L., Massa, E., Mudu, M. C., Mulas, C., Lusso, M. R., Gramignano, G., & Piras, M. R. (2001) · Journal of Molecular Medicine · doi:10.1007/s001090100234 · Cited by 91
“The biological effects of leptin/receptor interaction lead to a decrease in food intake and an increase in energy expenditure [3, 4, 7, 8] mediated by a leptin-induced decrease in the hypothalamic biosynthesis and release of the neuropeptide Y [4, 9], responsible for appetite stimulation, increase in food intake, insu…”
BackgroundAdipose tissue and reproduction in women
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Regulation of circulating leptin in humans
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“This occurs in leptin resistance (33) or under metabolic situations of low leptin levels such as those observed during the refeeding response following starvation (13).”
BackgroundEffects of central leptin administration on blood pressure in normotensive rats
Casto, R. M., VanNess, J. M., & Overton, J. M. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00223-7 · Cited by 91
Insulin resistance and bariatric surgery
Rao, R. S., Yanagisawa, R. T., & Kini, S. U. (2011) · Obesity Reviews · doi:10.1111/j.1467-789x.2011.00955.x · Cited by 91
“Leptin administration has however been shown to decrease insulin resistance in animal studies (41).”
BackgroundMetabolic Fuel and Clinical Implications for Female Reproduction
Mircea, C. N., Lujan, M. E., & Pierson, R. A. (2007) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/s1701-2163(16)32661-5 · Cited by 89
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“The effects of leptin administration on glucose homeostasis in polygenic models of type 2 diabetes have not been investigated because most models of type 2 diabetes have defects in leptin receptor signaling, such as the db/dbmouse and the Zucker diabetic fatty (ZDF) rats (30, 31).”
BackgroundRelation of Leptin to Insulin Resistance Syndrome in Children
Steinberger, J., Steffen, L. M., Jacobs, D. R., Moran, A., Hong, C.-P., & Sinaiko, A. R. (2003) · Obesity Research · doi:10.1038/oby.2003.153 · Cited by 89
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The effects of high fat diets on the blood–brain barrier transport of leptin: Failure or adaptation?
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“Among leptin's various functions are its ability to suppress appetite by stimulation of anorectics and inhibition of orexigens [6–9].”
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A Polymorphism in the Human Agouti-Related Protein Is Associated with Late-Onset Obesity
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Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism
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“In contrast to ghrelin, leptin inhibits and activates NPY/AgRp and POMC neurons, respectively [95, 111, 112].”
BackgroundDecreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats
Fernández‐Galaz, C., Fernández‐Agulló, T., Campoy, F., Arribas, C., Gallardo, N., Andrés, A., Ros, M., & Carrascosa, J. (2001) · Journal of Endocrinology · doi:10.1677/joe.0.1710023 · Cited by 84
Acute Effect of Leptin on Hepatic Glycogenolysis and Gluconeogenesis in Perfused Rat Liver
Nemecz, M., Preininger, K., Englisch, R., Fürnsinn, C., Schneider, B., Waldhäusl, W., & Roden, M. (1999) · Hepatology · doi:10.1002/hep.510290110 · Cited by 83
Alcoholism and obesity: overlapping neuropeptide pathways?
Thiele, T. E., Navarro, M., Sparta, D. R., Fee, J. R., Knapp, D. J., & Cubero, I. (2003) · Neuropeptides · doi:10.1016/j.npep.2003.10.002 · Cited by 81
The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective
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“Furthermore, the PVH CRH neuron may be regulated divergently by leptin in different species, as leptin increases CRH expression in the PVH in the rat [74, 75 ].”
BackgroundSchwartz, M. W., Erickson, J. C., Baskin, D. G., & Palmiter, R. D. (1998) · Endocrinology · doi:10.1210/endo.139.5.6000 · Cited by 83
Self-citationLeptin and other components of the Metabolic Syndrome in Mauritius—a factor analysis
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Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism
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The influence of obesity on hyperandrogenism and infertility in the female
Diamanti‐Kandarakis, E., & Bergiele, A. T. (2001) · Obesity Reviews · doi:10.1046/j.1467-789x.2001.00041.x · Cited by 82
“Leptin also modulates the activity of Neuropeptide Y and other peptides, such as galanin, in the hypothalamus that are known to affect eating behaviour (40).”
BackgroundLuque, R. M., Huang, Z., Shah, B., Mazzone, T., & Kineman, R. D. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00258.2006 · Cited by 81
“As previously reported (6, 15, 20, 48), treating ob/ob mice with leptin significantly reduced food intake and body weight Fig.”
Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction
Antonio Zorzano, A., & Claret, M. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00101 · Cited by 83
Does body mass play a role in the regulation of food intake?
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Metadata
- 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 › 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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