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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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“Leptin, an adipocytederived hormone, promotes anorexia, increases metabolism, and has also been found to activate the SNS.(34,35) Obese individuals have elevated levels of leptin, suggesting that they may have selective leptin resistance to its effect on appetite and metabolism, while preserving its renal/cardiovascul…”
BackgroundAdenovirus‐Mediated Leptin Expression Normalises Hypertension Associated with Diet‐Induced Obesity
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“enhances sympathetic nerve activity and norepinephrine turnover in iBAT (7, 15), thus 70 supporting a role of iBAT thermogenesis in leptin-induced body weight loss.”
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Effects of leptin on spinally projecting neurons in the PVN of the hypothalamus
Badoer, E., & Ryan, A. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01902-2 · Cited by 7
Spanswick, D. C., & Lee, K. (2003) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.8.1.217 · Cited by 7
“In relation to this, leptin and insulin receptors are highly expressed in the ARC [6,9,22], and both hormones have been shown to exert effects in this area [23-27].”
BackgroundThe Brainstem Is a Key Target for Neuroendocrine Research on Obesity
Takahashi, K. (2003) · Endocrinology · doi:10.1210/en.2003-0969 · Cited by 7
Mun, S., Park, K.-H., Kim, J.-K., Kim, J.-H., & Lee, S. (2024) · Scientific Reports · doi:10.1038/s41598-024-74619-7 · Cited by 11
“Leptin, a hormone produced by adipose tissue, also stimulates sympathetic nerve outflow, which can increase BP and HR 40 .”
BackgroundAltered frequency responses of sympathetic nerve discharge bursts after IL-1β and mild hypothermia
Kenney, M., Blecha, F., Fels, R. J., & Morgan, D. A. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01250.2001 · Cited by 6
“The splenic, renal, and lumbar nerves were isolated after a lateral incision (20–24), and the IBAT nerve was isolated after visualization of the IBAT after a nape incision (12).”
MethodSelf-citationdo Carmo, J. M., da Silva, A. A., Romero, D. G., & Hall, J. E. (2017) · The FASEB Journal · doi:10.1096/fj.201601224r · Cited by 6
Zhang, X., Hong, F., Qin, Z., Liu, L., Yang, J., Tang, X., Li, X., Zhang, J., & Luo, P. (2021) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3475 · Cited by 6
The potential role of the intestinal gut microbiota in obesity and the metabolic syndrome
Fava, F., Lovegrove, J. A., Tuohy, K. M., & Gibson, G. R. (2009) · Food Science & Technology Bulletin Functional Foods · doi:10.1616/1476-2137.15557 · Cited by 6
Nakamura, Y., Ueshima, H., Okuda, N., Miura, K., Kita, Y., Okamura, T., Turin, T. C., Okayama, A., Rodríguez, B. L., Curb, J. D., et al. (2010) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2010.03.004 · Cited by 5
“It acts on the hypothalamus, altering energy intake by decreasing appetite and increasing energy expenditure via sympathetic stimulation of several tissues [2].”
Tanida, M., Iwasaki, Y., & Yamamoto, N. (2019) · In Vivo · doi:10.21873/invivo.11675 · Cited by 6
Heusser, K., Tank, J., Diedrich, A., Fischer, A., Heise, T., & Jordan, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1107752 · Cited by 6
“activity through the leptin-melanocortin system (Haynes et al., 1997).”
BackgroundChildhood Obesity and Blood Pressure Regulation
Rocchini, A. P. (2010) · Humana Press eBooks · doi:10.1007/978-1-60327-824-9_17 · Cited by 6
Adiponectin Expression is Paradoxically Increased in Gold-thioglucose-induced Obesity
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Kataoka, Y., & Nicholls, S. J. (2014) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2014.975210 · Cited by 6
“While leptin has a variety of actions to control energy balance and metabolism [25,26], it has been also considered to promote atherosclerosis via various mechanisms.”
BackgroundMicrovascular Consequences of Obesity and Diabetes
Bohlen, H. G. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-374530-9.00021-8 · Cited by 5
Hernández, V. F., Kaur, K., ElSharief, M. W., Hajaj, S. W. A., Ebrahim, A. M., Razack, M., & Dragas, D. (2021) · Cureus · doi:10.7759/cureus.15766 · Cited by 6
The Autonomic Nervous System and Blood Pressure Regulation in the Elderly
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Abe, C., Nagai, Y., Yamaguchi, A., Aoki, H., Shimizu, S., Akiyama, T., Kawada, T., Sugimachi, M., & Morita, H. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00697.2014 · Cited by 5
Cardiovascular and Renal Actions of Leptin
Guha, P. K., Villarreal, D., Reams, G. P., & Freeman, R. H. (2003) · Progress in experimental cardiology · doi:10.1007/978-1-4419-9232-1_17 · Cited by 5
“In addition, there is increasing evidence suggesting that the biology of leptin extends to other organs including the kidney, the sympathetic nervous system and the systemic vasculature, where it may have prominent efIects [ 10-12 ].”
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Leptin rhythmicity and its relationship with other rhythm markers
Manzar, M. D., & Hussain, M. E. (2010) · Biological Rhythm Research · doi:10.1080/09291011003759558 · Cited by 5
“Conversely, the effect of leptin on catecholamines has shown that it increases noradrenaline turnover in thermogenic interscapular BAT (Collins et al. 1996) and also increases the sympathetic outflow to other tissues (Dunbar et al. 1997; Haynes et al. 1997).”
BackgroundInfluentialDevelopmental and food-access-dependent changes in effector systems activated by leptin
Eiden, S., Doering, H., & Schmidt, I. (2002) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-002-0944-4 · Cited by 5
“On the other hand, mice with free access to the standard rodent diet (a monotonous high-carbohydrate, high-fiber diet) responded to leptin by decreasing their FI markedly; however, their MR slightly decreased rather than increased, indicating for rodents having free access to the standard laboratory diet that any pote…”
BackgroundModulation of Lung Allergic Inflammation and Malnutrition
Landgraf, M. A., Landgraf, R. G., de Carvalho, M. H. C., & Fortes, Z. B. (2008) · NeuroImmunoModulation · doi:10.1159/000154248 · Cited by 5
“Studies on both leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice have illustrated the diverse functions of leptin, as revealed by the findings of marked abnormalities in neuroendocrine function [”
BackgroundRelation of Serum Leptin to Blood Pressure of Japanese in Japan and Japanese-Americans in Hawaii
Nakamura, Y., Ueshima, H., Okuda, N., Murakami, Y., Miura, K., Kita, Y., Okamura, T., Turin, T. C., Rodríguez, B. L., Curb, J. D., et al. (2009) · Hypertension · doi:10.1161/hypertensionaha.109.133074 · Cited by 5
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Hypothalamic Origin of Prevalent Human Disease
Björntorp, P. A. (2002) · Elsevier eBooks · doi:10.1016/b978-012532104-4/50104-9 · Cited by 5
Zhang, X., Tian, L., Majumdar, A., & Scheller, E. L. (2024) · Comprehensive physiology · doi:10.1002/cphy.c230016 · Cited by 23
Central leptin pathways in metabolic homeostasis
Zhao, Y., Laule, C. F., & Rahmouni, K. (2025) · Clinical Science · doi:10.1042/cs20257748 · Cited by 5
“Leptin’s sympathoexcitatory actions regulate adipose tissue gene programs to promote lipid utilization through the SNS [123–125].”
Dodson, A. D., Herbertson, A. J., Honeycutt, M. K., Vered, R., Slattery, J. D., Goldberg, M., Tsui, E. W., Wolden‐Hanson, T., Graham, J. L., Wietecha, T., et al. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46100679 · Cited by 4
“…in skeletal muscle [22,23] and/or through the anabolic effects of OT on muscle [24,25], (5) white adipose tissue thermogenesis or (6) hormonal mediators (e.g., fibroblast growth factor-21 [26], irisin [27], leptin [28], thyroid hormone [29] or secretin [30,31] (see [32,33] for review).”
BackgroundEdwards, M. M., Nguyen, H. K., Dodson, A. D., Herbertson, A. J., Honeycutt, M. K., Slattery, J. D., Rambousek, J. R., Tsui, E. W., Wolden‐Hanson, T., Wietecha, T., et al. (2024) · Frontiers in Drug Delivery · doi:10.3389/fddev.2024.1497746 · Cited by 4
Korać, A., Buzadžić, B., Otašević, V., Vasilijević, A., Janković, A., & Korać, B. (2008) · Folia Histochemica et Cytobiologica · doi:10.2478/v10042-008-0015-6 · Cited by 4
Regulación de la ingesta alimentaria: una perspectiva clínica
Salvador, J., & Frühbeck, G. (2005) · Endocrinología y Nutrición · doi:10.1016/s1575-0922(05)71040-8 · Cited by 4
Leptin, sympathetic and baroreflex function: another step on the road to sympathetic differentiation
Grassi, G. M., & Elam, M. (2002) · Journal of Hypertension · doi:10.1097/00004872-200208000-00008 · Cited by 4
Hypertension Research in Sleep Apnea
Hargens, T. A., Nickols‐Richardson, S. M., Gregg, J. M., Zedalis, D., & Herbert, W. G. (2006) · Journal of Clinical Hypertension · doi:10.1111/j.1524-6175.2006.05694.x · Cited by 4
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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