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Receptor-mediated regional sympathetic nerve activation by leptin.
Open accessAbstract
Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.
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In the citing paper
“These findings are in contrast to the effect of leptin administration on increase natriuresis (49, 50) and sympathetic activity (51) in normal, nonobese leptin-resistant Zucker rats (51).”
From The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men (2003) · cites this paper as [51]
Experimental — accuracy not yet measuredIn the citing paper
“Plasma leptin concentration is highly correlated with SNA activity123, and acute leptin infusions increase SNA in the brown adipose tissue, adrenal glands and kidneys of rodents124.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [124]
In the citing paper
“acute leptin administration in rodents increased SNS activity in brown adipose tissue (BAT), the adrenal gland, and the kidneys84.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [84]
In the citing paper
“Acute leptin administration in rodents and humans increases renal and muscle SNS activity [45, 46] while chronic increases in plasma leptin levels, comparable to those found in severe obesity, caused sustained increases in BP and HR in rodents despite causing weight loss which would normally reduce BP [47].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [45]
In the citing paper
“In addition its effects on appetite and metabolism, leptin acts in the brain to produce receptor-mediated increases in regional sympathetic activity91.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [91]
In the citing paper
“Leptin is a potent appetite suppressant and, like insulin, stimulates the SNS.24,25”
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“, 1995) ? " SNS activity (Haynes et al., 1997) ? # HPA activity (Heiman et al.”
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“A study conducted in non-obese rats reported that intravenous or intracerebroventricular (ICV) infusions of leptin increase sympathetic activity in the kidneys and adrenal glands [29].”
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“Leptin injection either centrally or peripherally increases sympathetic nerve activity to BAT (Collins and Surwit, 1996; Haynes et al., 1997), and expression of uncoupling protein 1 (UCP-1), increasing heat production.”
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“In the present study, we could not find any correlation between the diurnal rhythm of serum leptin levels and LF/HF values in the study population, although the direct sympathoexcitatory effects of leptin have been reported in animal studies ( 39 ).”
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“In fact, leptin has been shown to stimulate sympathetic nervous system (SNS) activity in thermogenic (2) and nonthermogenic organs ( 3 ) in animal models.”
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BackgroundInteractions between central nervous system and peripheral metabolic organs
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“…metabolic stimuli such as leptin, the hormone produced by white adipocytes, can also increase sympathetic activity to the BAT, resulting in upregulated expression of UCP1 and enhanced thermogenic capability (Collins et al., 1996; Haynes et al., 1997; Jiang et al., 2020; Scarpace and Matheny, 1998).”
BackgroundUCP2, UCP3 and leptin gene expression: modulation by food restriction and leptin
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“Leptin increases sympathetic nerve activity and norepinephrine turnover in BAT (Collins et al. 1996, Haynes et al. 1997).”
Dietary vitamin A supplementation in rats: suppression of leptin and induction of UCP1 mRNA
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Adipocytokines, cardiovascular pathophysiology and myocardial protection
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“In addition to a reduction in appetite and food intake, activation of central leptin receptors leads to an increase in energy expenditure, which, in small mammals and the young of larger mammals, occurs, at least in part, through an increase in the sympathetic outflow to brown adipose tissue (BAT) (17) and the resulti…”
BackgroundEffects of central leptin administration on blood pressure in normotensive rats
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Leptin directly stimulates thermogenesis in skeletal muscle
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“Such sympathetic activation is not observed in obese Zucker rats possessing a leptin receptor gene mutation [ 31 ], indicating that leptin-mediated increases in central sympathetic outfl ow require the presence of an intact leptin receptor.”
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“ist as well; leptin, the protein product of the ob/ob gene, also stimulates the SNS while suppressing appetite (Dunbar et al., 1997; Haynes et al., 1997).”
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“Leptin was shown to enhance sympathetic outflow to BAT (2, 11) and increase UCP mRNA levels in BAT (29, 34).”
BackgroundPlasma Leptin and Blood Pressure in Men: Graded Association Independent of Body Mass and Fat Pattern
Barba, G., Russo, O., Siani, A., Iacone, R., Farinaro, E., Gerardi, M. C., Russo, P., Valle, E. D., & Strazzullo, P. (2003) · Obesity Research · doi:10.1038/oby.2003.25 · Cited by 88
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Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations
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Seasonal hypothermia in a large migrating bird: saving energy for fat deposition?
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“Decreased levels of leptin might also result in anti-hypertensive effects by reducing RSNS and RAAS activation 28,39,40,60 .”
Hypothalamic melanocortin neurons integrate signals of energy state
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Direct and indirect effects of leptin on preadipocyte proliferation and differentiation
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“Although leptin has been reported to stimulate sympathetic outflow to some tissues (29) and that increased sympathetic activity inhibits adipocyte proliferation (10), this mechanism cannot account for changes in cell number in an in vitro condition.”
BackgroundCentral effects of leptin on cardiovascular and neurohormonal responses in conscious rabbits
Matsumura, K., Abe, I., Tsuchihashi, T., & Fujishima, M. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.278.5.r1314 · Cited by 83
“Not only leptin but also neuropeptide Y and corticotrophin-releasing factor have been shown to influence sympathetic nerve activity to brown adipose tissue, thereby increasing thermogenesis (10, 11, 22).”
BackgroundResultInfluentialEvidence for Leptin Regulation of Food Intake in Humans1
Larsson, H., Elmståhl, S., Berglund, G. L., & Åhrén, B. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.12.5342 · Cited by 83
“Thus, leptin administration inhibits food intake (1, 2) through a central effect on leptin receptors in the hypothalamus (3, 4), and increases energy expenditure through activating the sympathetic nervous system (5, 6) and uncoupling protein-2 (7, 8).”
Prpić, V., Watson, P. M., Frampton, I. C., Sabol, M. A., Jezek, G. E., & Gettys, T. W. (2003) · Endocrinology · doi:10.1210/en.2002-220835 · Cited by 82
Cardiovascular effects of leptin and orexins
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“Orexins were first characterized as stimulators of appetite and food consumption (76, 84); on the other hand, leptin was suspected to reduce food intake, mainly acting on neurons in the arcuate nucleus of the hypothalamus (103), and increase energy expenditure (18, 35).”
BackgroundInfluentialAcute 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
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Wavelet Methods for Spike Detection in Mouse Renal Sympathetic Nerve Activity
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“Similarly, investigators studying the rat RSNA have used the highest voltage in the postmortem recording as a threshold for a subsequent off-line amplitude discrimination procedure [21].”
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Metadata
- Authors
- Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L., & Sivitz, W. I.
- Affiliations
- University of Iowa (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1997-07-15
- Volume
- 100
- Issue
- 2
- Pages
- 270-278
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508189
- OpenAlex
- W2061340727
- Cited by
- 979
- References
- 29
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 17 · 2023: 11 · 2022: 14 · 2021: 17 · 2020: 15 · 2019: 13 · 2018: 11 · 2017: 31 · 2016: 29 · 2015: 25 · 2014: 44 · 2013: 34 · 2012: 43
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Wellcome Trust
- National Institutes of Health (5p50hl044546-05, 5r29hl043514-05)
- National Heart, Lung, and Blood Institute (HL-43514, HL-44546)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-25295, P30DK025295)
- 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 › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- leptin, sympathetic activity, brown adipose tissue, renal sympathetic nerve activity, adrenal gland, thermogenesis, leptin receptor, Zucker fatty rats, norepinephrine, energy homeostasis
- MeSH terms
- Action Potentials, Adrenal Glands, Animals, Blood Glucose, Adipose Tissue, Brown, Disease Models, Animal, Hemodynamics, Hindlimb, Insulin, Kidney, Male, Obesity, Proteins, Rats, Zucker, Sympathetic Nervous System, Rats, Sprague-Dawley, Leptin, Rats
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