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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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“In 1997, Haynes et al.(19) first demonstrated that centrally administered leptin stimulates the sympathetic nervous system (SNS).”
BackgroundInfluentialSelective Resistance to Central Neural Administration of Leptin in Agouti Obese Mice
Rahmouni, K., Haynes, W. G., Morgan, D. A., & Mark, A. L. (2002) · Hypertension · doi:10.1161/hy0202.102836 · Cited by 126
Self-citationHypertension in Obesity and the Leptin Receptor Gene Locus1
Rosmond, R., Chagnon, Y. C., Holm, G., Chagnon, M., Përusse, L., Lindell, K., Carlsson, B., Bouchard, C., & Björntorp, P. A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.9.6781 · Cited by 126
“As mentioned in the introduction, leptin is believed to interact with the central sympathetic nervous system (8, 9 ). In addition, blood pressure increases with infusion of leptin”
BackgroundInfluentialBurwell, R. G., Aujla, R. K., Grevitt, M. P., Dangerfield, P., Moulton, A., Randell, T. L., & Anderson, S. (2009) · Scoliosis · doi:10.1186/1748-7161-4-24 · Cited by 130
Interaction between leptin and sympathetic nervous system in hypertension
Haynes, W. G. (2000) · Current Hypertension Reports · doi:10.1007/s11906-000-0015-1 · Cited by 124
Self-citationDoes Leptin Cause Vascular Disease?
Cooke, J. P., & Oka, R. K. (2002) · Circulation · doi:10.1161/01.cir.0000036864.14101.1b · Cited by 124
Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome
Correia, M. L. G., & Rahmouni, K. (2006) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2005.00562.x · Cited by 121
Martínez‐Sánchez, N., Sweeney, O., Sidarta-Oliveira, D., Caron, A., Stanley, S. A., & Domingos, A. I. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.017 · Cited by 127
Fortuño, A., Rodrı́guez, A., Gómez‐Ambrosi, J., Frühbeck, G., & Dı́ez, J. (2003) · Journal of Physiology and Biochemistry · doi:10.1007/bf03179868 · Cited by 123
Velkoska, E., Cole, T. J., & Morris, M. J. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00505.2004 · Cited by 128
“Obesity related increases in blood pressure can also be associated with hyperleptinaemia (17, 36), possibly due to the increased sympathetic activity to the iBAT, kidney and adrenal (27).”
BackgroundObesity: A neuroimmunometabolic perspective
Larabee, C. M., Neely, O. C., & Domingos, A. I. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0283-6 · Cited by 123
Electrophysiological Actions of Peripheral Hormones on Melanocortin Neurons
Cowley, M. A., Cone, R. D., Enriori, P. J., Louiselle, I., Williams, S., & Evans, A. E. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb03178.x · Cited by 122
Relationships of Cardiac Autonomic Function With Metabolic Abnormalities in Childhood Obesity
Kaufman, C. L., Kaiser, D. R., Steinberger, J., Kelly, A. S., & Dengel, D. R. (2007) · Obesity · doi:10.1038/oby.2007.619 · Cited by 120
“Leptin is an adipocyte-derived protein hormone that carries out its primary task of regulating food intake and energy homeostasis [via increased sympathetic nervous system (SNS) outflow] by binding to specific leptin receptors in the hypothalamus (8,9).”
BackgroundIntracellular Mechanisms Involved in Leptin Regulation of Sympathetic Outflow
Rahmouni, K., Haynes, W. G., Morgan, D. A., & Mark, A. L. (2003) · Hypertension · doi:10.1161/01.hyp.0000048342.54392.40 · Cited by 120
Self-citationA brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity
Hilzendeger, A. M., Morgan, D. A., Brooks, L. A., Dellsperger, D., Liu, X., Grobe, J. L., Rahmouni, K., Sigmund, C. D., & Mark, A. L. (2012) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00974.2011 · Cited by 118
“In addition to decreasing food intake, leptin increases sympathetic nerve activity (SNA) to thermogenic brown adipose tissue (BAT) and to nonthermogenic tissues such as the kidney (13, 26).”
BackgroundSelf-citationBrain metabolic sensing and metabolic signaling at the level of an astrocyte
Marina, N., Turovsky, E. A., Christie, I. N., Hosford, P. S., Hadjihambi, A., KORSAK, A. S., Ang, R., Mastitskaya, S., SheikhBahaei, S., Theparambil, S. M., et al. (2017) · Glia · doi:10.1002/glia.23283 · Cited by 124
Frühbeck, G. (2001) · Proceedings of The Nutrition Society · doi:10.1079/pns200196 · Cited by 120
“However, this generalized sympathoexcitation was not always followed by an increase in arterial pressure (Haynes et al .”
BackgroundOxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension
Bełtowski, J., Wójcicka, G., Marciniak, A., & Jamroz, A. (2004) · Life Sciences · doi:10.1016/j.lfs.2003.10.029 · Cited by 118
da Silva, A. A., Kuo, J. J., & Hall, J. E. (2004) · Hypertension · doi:10.1161/01.hyp.0000128421.23499.b9 · Cited by 117
“9% saline vehicle ICV for 12 days plus leptin (1 g/kg per minute IV, n 5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 g/kg per minute IV, n 6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n 8) for 12 days.”
Role of leptin resistance in the development of obesity in older patients
Picard, F., Carter, S., Caron, A., & Richard, D. (2013) · Clinical Interventions in Aging · doi:10.2147/cia.s36367 · Cited by 134
“Moreover, SNS activation by leptin goes beyond BAT thermogenesis, since leptin administration can increase heart rate and blood pressure in a dose-dependent manner.(63,64) Elevated plasma leptin levels increase blood pressure in mice and”
Role of leptin in obesity‐related hypertension
Haynes, W. G. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.031237 · Cited by 117
“In animal studies, leptin increases sympathetic nerve activity to the kidneys, hindlimb and adrenal glands (Haynes et al. 1997).”
BackgroundSelf-citationMuscle metaboreflex control is diminished in normotensive obese women
Negrão, C. E., Trombetta, I. C., Batalha, L. T., Ribeiro, M. M., Rondon, M. U. P. B., Tinucci, T., Forjaz, C. L. M., Barretto, A. C. P., Halpern, A., & Villares, S. M. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.2.h469 · Cited by 116
“First, besides its effect on appetite and thermogenesis control, leptin, which is augmented in obesity, increases norepinephrine turnover in brown adipose tissue (2), and increases sympathetic nerve activity to brown adipose tissue (11), kidneys, adrenal glands, and hindlimbs (11).”
BackgroundInhibition of NO Synthesis Enhances Chronic Cardiovascular and Renal Actions of Leptin
Kuo, J. J., Jones, O. B., & Hall, J. E. (2001) · Hypertension · doi:10.1161/01.hyp.37.2.670 · Cited by 114
Lieb, D. C., Parson, H. K., Mamikunian, G., & Vinik, A. I. (2011) · Experimental Diabetes Research · doi:10.1155/2012/878760 · Cited by 114
“Intravenous leptin infusion has been shown to stimulate SNS activity in animal models [33].”
BackgroundObesity-associated activation of angiotensin and endothelin in the cardiovascular system
Barton, M., Carmona, R., Ortmann, J., Krieger, J. E., & Traupe, T. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00307-2 · Cited by 113
Mitochondrial Uncoupling Proteins in Energy Expenditure
Kozak, L. P., & Harper, M. (2000) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.20.1.339 · Cited by 111
Interactions between the sympathetic nervous system and the kidneys in arterial hypertension
Grisk, O. (2003) · Cardiovascular Research · doi:10.1016/j.cardiores.2003.11.024 · Cited by 114
Regulation of leptin production: a dominant role for the sympathetic nervous system?
Trayhum, P., Duncan, J. S., Hoggard, N., & Rayner, D. V. (1998) · Proceedings of The Nutrition Society · doi:10.1079/pns19980060 · Cited by 113
Leptin: At the crossroads of energy balance and systemic inflammation
Steiner, A. A., & Romanovsky, A. A. (2006) · Progress in Lipid Research · doi:10.1016/j.plipres.2006.11.001 · Cited by 112
“Only when injected at doses known [66] to produce supraphysiological rises in its plasma level (to > 100 ng/ml) does leptin cause marked hypermetabolic and anorexic responses in fed subjects [67,68].”
BackgroundLeptin and the Cardiovascular System
Rahmouni, K. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.225 · Cited by 110
“MECHANISMS OF LEPTIN-INDUCED SYMPATHOACTIVATION The receptor-mediated sympathoexcitatory effect of leptin is supported by the absence of SNA response to leptin in obese Zucker rats (Haynes et al., 1997).”
BackgroundMethodInfluentialMancuso, P., Rahman, A., Hershey, S. D., Dandu, L., Nibbelink, K. A., & Simpson, R. U. (2008) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181761906 · Cited by 111
A putative role for cytokines in the impaired appetite in depression
Andréasson, A., Arborelius, L., Erlanson‐Albertsson, C., & Lekander, M. (2006) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2006.08.002 · Cited by 108
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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