Control of Blood Pressure, Appetite, and Glucose by Leptin in Mice Lacking Leptin Receptors in Proopiomelanocortin Neurons
Open accessAbstract
Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR flox/flox /POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR flox/flox /POMC-Cre, wild-type, LepR flox/flox , and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR flox/flox /POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR flox/flox , and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR flox/flox /POMC-Cre mice had normal MAP and heart rate compared with LepR flox/flox but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR flox/flox /POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR flox/flox /POMC-Cre mice. Leptin increased oxygen consumption in LepR flox/flox /POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption.
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Selective leptin receptor deletion in POMC neurons of the arcuate nucleus and brainstem abolished blood pressure increases in mice during chronic leptin infusions.
“Selective LepR deletion in POMC neurons of the ARC and brainstem also abolished BP increases in mice during chronic leptin infusions140.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [140]
Deletion of LepR only in POMC neurons prevents increased BP during chronic hyperleptinemia.
“In fact, deletion of LepR only in POMC neurons, a major type of neuron in the ARC, prevents increased BP during chronic hyperleptinemia97.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [97]
Leptin receptor deletion specifically in POMC neurons did not markedly attenuate the effects of leptin on food intake.
“Leptin receptor (LR) deletion specifically in POMC neurons completely abolished the chronic effects of leptin to raise BP and to reduce plasma glucose and insulin levels but did not markedly attenuate the effects of leptin on food intake [50].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [50]
Leptin receptor activation in POMC neurons is critical for leptin's ability to increase blood pressure and improve glucose homeostasis but not for its effect to reduce food intake.
“These findings suggest that LR activation in POMC neurons is critical for leptin’s ability to increase BP and improve glucose homeostasis but not for its effect to reduce food intake.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [50]
Leptin requires activation of POMC neurons and MC4R to mediate its effects on renal sympathetic nervous system activity and blood pressure.
“Leptin requires activation of POMC neurons and MC4R to mediate its effects on renal SNS activity and BP [28, 50, 51].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [50]
Leptin receptor deletion specifically in POMC neurons completely abolished the chronic effects of leptin to raise blood pressure and to reduce plasma glucose and insulin levels.
“Leptin receptor (LR) deletion specifically in POMC neurons completely abolished the chronic effects of leptin to raise BP and to reduce plasma glucose and insulin levels but did not markedly attenuate the effects of leptin on food intake [50].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [50]
Mice lacking leptin signaling in POMC neurons or in the arcuate nucleus of the hypothalamus through deletion of the leptin receptor itself or components of its signaling pathway such as STAT3 are protected against obesity-associated hypertension.
“Similarly, mice lacking leptin signaling in POMC neurons or in the arcuate nucleus of the hypothalamus, where most POMC neurons reside, through deletion of the leptin receptor itself (39;40) or components of its signaling pathway such as the signal transducer and activator of transcription-3 (41) are protected against obesity-associated hypertension.”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [39]
Disruption of leptin receptor signaling in POMC neurons abolished the ability of exogenous leptin administration to increase blood pressure.
“Disruption of leptin receptor signaling in POMC neurons abolished the ability of exogenous leptin administration to increase blood pressure (39;41) which provides additional support to the notion that leptin is a critical hormone in coupling hypertension and obesity (Figure 1).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [39]
Leptin is a critical hormone in coupling hypertension and obesity.
“Disruption of leptin receptor signaling in POMC neurons abolished the ability of exogenous leptin administration to increase blood pressure (39;41) which provides additional support to the notion that leptin is a critical hormone in coupling hypertension and obesity (Figure 1).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [39]
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Harlan, S. M., & Rahmouni, K. (2012) · Clinical Autonomic Research · doi:10.1007/s10286-012-0168-4 · Cited by 39 · see citing works
do Carmo, J. M., da Silva, A. A., Rushing, J. S., Pace, B., & Hall, J. E. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00518.2012 · Cited by 38 · see citing works
Self-citationRole of the brain melanocortins in blood pressure regulation
do Carmo, J. M., da Silva, A. A., Wang, Z., Fang, T., Aberdein, N., Perez de Lara, C. E., & Hall, J. E. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.03.003 · Cited by 38 · see citing works
Self-citationControl of metabolic and cardiovascular function by the leptin–brain melanocortin pathway
do Carmo, J. M., da Silva, A. A., Dubinion, J., Sessums, P. O., Ebaady, S. H., Wang, Z., & Hall, J. E. (2013) · IUBMB Life · doi:10.1002/iub.1187 · Cited by 36 · see citing works
Self-citationFactors Responsible for Obesity-Related Hypertension
Lim, K., Jackson, K. L., Sata, Y., & Head, G. A. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0750-1 · Cited by 35 · see citing works
Bassi, M., Nakamura, N. B., Furuya, W. I., Colombari, D. S. A., Menani, J. V., do Carmo, J. M., da Silva, A. A., Hall, J. E., & Colombari, E. (2014) · Acta Physiologica · doi:10.1111/apha.12394 · Cited by 34 · see citing works
Self-citationRecent Advances in Neurogenic Hypertension
Stocker, S. D., Kinsman, B. J., & Sved, A. F. (2017) · Hypertension · doi:10.1161/hypertensionaha.117.08936 · Cited by 34 · see citing works
Control of respiratory and cardiovascular functions by leptin
Bassi, M., Furuya, W. I., Zoccal, D. B., Menani, J. V., Colombari, E., Hall, J. E., da Silva, A. A., do Carmo, J. M., & Colombari, D. S. A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.01.019 · Cited by 33 · see citing works
Self-citationHall, M. E., & Hall, J. E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-42973-3.00005-6 · Cited by 33 · see citing works
Self-citationLeptin: Master Regulator of Biological Functions that Affects Breathing
Gauda, E. B., Conde, S. V., Bassi, M., Zoccal, D. B., Colombari, D. S. A., Colombari, E., & Despotovic, N. (2020) · Comprehensive physiology · doi:10.1002/cphy.c190031 · Cited by 32 · see citing works
Dubinion, J. H., do Carmo, J. M., Adi, A., Hamza, S., da Silva, A. A., & Hall, J. E. (2013) · Hypertension · doi:10.1161/hypertensionaha.111.00020 · Cited by 31 · see citing works
Self-citationSerum Leptin Levels and the Risk of Stroke
Saber, H., Himali, J. J., Shoamanesh, A., Beiser, A., Pikula, A., Harris, T. B., Roubenoff, R., Romero, J. R., Kase, C. S., Vasan, R. S., et al. (2015) · Stroke · doi:10.1161/strokeaha.115.009463 · Cited by 31 · see citing works
do Carmo, J. M., da Silva, A. A., Wang, Z., Freeman, J. N., Alsheikh, A. J., Adi, A. H., & Hall, J. E. (2015) · Hypertension · doi:10.1161/hypertensionaha.115.06153 · Cited by 30 · see citing works
Self-citationCNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System
da Silva, A. A., do Carmo, J. M., & Hall, J. E. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01311-1 · Cited by 30 · see citing works
Self-citationdo Carmo, J. M., da Silva, A. A., Sessums, P. O., Ebaady, S. H., Pace, B. R., Rushing, J. S., Davis, M. T., & Hall, J. E. (2014) · International Journal of Obesity · doi:10.1038/ijo.2013.177 · Cited by 26 · see citing works
Self-citationBruder-Nascimento, T. B., Butler, B. R., Herren, D. J., Brands, M. W., Bence, K. K., & de Chantemèle, E. J. B. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.10.012 · Cited by 26 · see citing works
Sex Differences in Leptin Control of Cardiovascular Function in Health and Metabolic Diseases
de Chantemèle, E. J. B. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-70178-3_6 · Cited by 25 · see citing works
Liu, D., Guan, L., Zhao, Y., Liu, Y., Sun, X., Li, H., Yin, Z., Li, L., Ren, Y., Wang, B., et al. (2020) · Hypertension Research · doi:10.1038/s41440-020-0439-8 · Cited by 25 · see citing works
Gava, F. N., da Silva, A. A., Dai, X., Harmancey, R., Ashraf, S., Omoto, A. C. M., Salgado, M. C., Moak, S. P., Li, X., Hall, J. E., et al. (2021) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2020.11.007 · Cited by 24 · see citing works
Self-citationTong, X., Hou, L., He, W., Mei, C., Huang, B., Zhang, C., Hu, C. Y., & Wang, C. (2020) · Scientific Reports · doi:10.1038/s41598-020-66061-2 · Cited by 23 · see citing works
Direct Recording of Renal Sympathetic Nerve Activity in Unrestrained, Conscious Mice
Hamza, S. M., & Hall, J. E. (2012) · Hypertension · doi:10.1161/hypertensionaha.111.186577 · Cited by 22 · see citing works
Self-citationÇakır, I., Martinez, M. D., Pan, P. L., Welch, E. B., Patel, S. H., & Ghamari‐Langroudi, M. (2019) · Endocrinology · doi:10.1210/en.2019-00062 · Cited by 22 · see citing works
Aberdein, N., Dambrino, R. J., do Carmo, J. M., Wang, Z., Mitchell, L. E., Drummond, H. A., & Hall, J. E. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00287.2017 · Cited by 21 · see citing works
Self-citationXie, Y., Bo, L., Jiang, S., Tian, Z., Kan, H., Li, Y., Song, W., & Zhao, J. (2016) · Environmental Science and Pollution Research · doi:10.1007/s11356-015-5933-1 · Cited by 21 · see citing works
da Silva, A. A., Spradley, F. T., Granger, J. P., Hall, J. E., & do Carmo, J. M. (2015) · Journal of Neurophysiology · doi:10.1152/jn.00911.2014 · Cited by 21 · see citing works
Self-citationLeptin regulates CD16 expression on human monocytes in a sex-specific manner
Cannon, J. G., Sharma, G. K., Sloan, G. J., Dimitropoulou, C., Baker, R. R., Mazzoli, A., Kraj, B., Mulloy, A. L., & Cortez‐Cooper, M. Y. (2014) · Physiological Reports · doi:10.14814/phy2.12177 · Cited by 21 · see citing works
Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure
Steinbrekera, B., & Roghair, R. D. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0273 · Cited by 21 · see citing works
Does leptin cause an increase in blood pressure in animals and humans?
Simonds, S. E., Pryor, J. T., & Cowley, M. A. (2016) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000287 · Cited by 20 · see citing works
do Carmo, J. M., da Silva, A. A., Gava, F. N., Moak, S. P., Dai, X., & Hall, J. E. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00077.2019 · Cited by 19 · see citing works
Self-citationLeptin and Associated Neural Pathways Underlying Obesity‐Induced Hypertension
Laule, C. F., & Rahmouni, K. (2024) · Comprehensive physiology · doi:10.1002/cph4.8 · Cited by 18 · see citing works
Reprint of: Recent Updates on Obesity Treatments: Available Drugs and Future Directions
Dragano, N. R. V., Fernø, J., Diéguez, C., López, M., & Milbank, E. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.08.009 · Cited by 18 · see citing works
Animal Models in Obesity and Hypertension
Segal‐Lieberman, G., & Rosenthal, T. (2013) · Current Hypertension Reports · doi:10.1007/s11906-013-0338-3 · Cited by 17 · see citing works
Inhibitor κB Kinase 2 Is a Myosin Light Chain Kinase in Vascular Smooth Muscle
Ying, Z., do Carmo, J. M., Xiang, L., da Silva, A. A., Chen, M., Ryan, M. J., Ostrowski, M. C., Rajagopalan, S., & Hall, J. E. (2013) · Circulation Research · doi:10.1161/circresaha.113.301510 · Cited by 17 · see citing works
Self-citationRole of SOCS3 in POMC neurons in metabolic and cardiovascular regulation
Wang, Z., do Carmo, J. M., da Silva, A. A., Bailey, K. C., Aberdein, N., Moak, S. P., & Hall, J. E. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00163.2018 · Cited by 17 · see citing works
Self-citationMolecular Mechanisms of Sodium-Sensitive Hypertension in the Metabolic Syndrome
Nizar, J. M., & Bhalla, V. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0759-5 · Cited by 16 · see citing works
da Silva, A. A., Hall, J. E., & do Carmo, J. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184805 · Cited by 16 · see citing works
Self-citationPeripheral leptin signaling persists in innate immune cells during diet-induced obesity
Souza-Almeida, G., Palhinha, L., Liechocki, S., Pereira, J. A. D. S., Reis, P. A., Dib, P. R. B., Hottz, E. D., Gameiro, J., Vallochi, A. L., de Almeida, C. J., et al. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ab0820-092rr · Cited by 15 · see citing works
da Silva, A. A., Moak, S. P., Dai, X., Borges, G. C., Omoto, A. C. M., Wang, Z., Li, X., Mouton, A. J., Hall, J. E., & do Carmo, J. M. (2022) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00300.2021 · Cited by 13 · see citing works
Self-citationSuazo, J., Hodgson, M. I., Obregón, A. M., Valladares, M., Gerardo Weisstaub, N., Amador, P., & Santos, J. L. (2013) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2013-0084 · Cited by 13 · see citing works
Role of autonomic nervous system in chronic CNS-mediated antidiabetic action of leptin
da Silva, A. A., Hall, J. E., Moak, S. P., Browning, J. R., Houghton, H. J., Micheloni, G. C., & do Carmo, J. M. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00301.2016 · Cited by 13 · see citing works
Self-citationYalamanchili, C., Chittiboyina, A. G., Haider, S., Vásquez, Y., Khan, S. I., do Carmo, J. M., da Silva, A. A., Pinkerton, M., Hall, J. E., Walker, L., et al. (2019) · Heliyon · doi:10.1016/j.heliyon.2019.e02782 · Cited by 13 · see citing works
Self-citationDrug Discovery for Diabetic Nephropathy: Trying the Leap From Mouse to Man
Breyer, M. D. (2012) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2012.07.007 · Cited by 12 · see citing works
do Carmo, J. M., da Silva, A. A., Freeman, J. N., Wang, Z., Moak, S. P., Hankins, M. W., Drummond, H. A., & Hall, J. E. (2018) · Hypertension · doi:10.1161/hypertensionaha.118.11127 · Cited by 11 · see citing works
Self-citationHigh leptin level and leptin receptor Lys656Asn variant are risk factors for preeclampsia
Wang, S., Qiao, F. Y., & Feng, L. (2013) · Genetics and Molecular Research · doi:10.4238/2013.january.4.14 · Cited by 11 · see citing works
Physiology and Pathophysiology of Hypertension
Hall, J. E., Granger, J. P., & Hall, M. E. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381462-3.00039-2 · Cited by 11 · see citing works
Self-citationda Silva, A. A., Freeman, J. N., Hall, J. E., & do Carmo, J. M. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00293.2017 · Cited by 11 · see citing works
Self-citationFrom pathophysiology to novel approaches for obesity-associated hypertension
Kanbay, M., Yayci, E., Genc, C., Copur, S., Aktaş, Ö. Y., Sarafidis, P. A., Covic, A. C., Ortíz, A., & Laffin, L. J. (2025) · Clinical Kidney Journal · doi:10.1093/ckj/sfaf218 · Cited by 10 · see citing works
Morais, R. L., Hilzendeger, A. M., Visniauskas, B., Todiraş, M., Alenina, N. V., Mori, M. A., Araújo, R. C., Nakaie, C. R., Chagas, J. R., Carmona, A. K., et al. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00485.2016 · Cited by 10 · see citing works
do Carmo, J. M., Hall, J. E., Dai, X., Aitken, N. M., Larson, K., Luna-Suarez, E. M., Wang, Z., Omoto, A. C. M., Mouton, A. J., Li, X., et al. (2024) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00294.2023 · Cited by 9 · see citing works
Self-citationMori, F.-K., & Shimosawa, T. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26010420 · Cited by 9 · see citing works
do Carmo, J. M., da Silva, A. A., Moak, S. P., Browning, J. R., Dai, X., & Hall, J. E. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.09.034 · Cited by 9 · see citing works
Self-citationRole of the Melanocortin System in the Central Regulation of Cardiovascular Functions
Copperi, F., Kim, J. D., & Diano, S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725709 · Cited by 9 · see citing works
Metabolic Signaling to the Central Nervous System: Routes Across the Blood Brain Barrier
Smith, P., & Ferguson, A. V. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990560 · Cited by 9 · see citing works
Obesity and Metabolic Syndrome Hypertension
Hall, M. E., Wang, Z., do Carmo, J. M., Kamimura, D., & Hall, J. E. (2018) · Updates in hypertension and cardiovascular protection · doi:10.1007/978-3-319-59918-2_42 · Cited by 8 · see citing works
Self-citationAl‐Daghri, N. M., Dahman, L. S. B., Al-Attas, O. S., Saleem, T. H., Alokail, M. S., Alkharfy, K. M., Draz, H. M., Yakout, S. M., Mohamed, A. O., Harte, A. L., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051255 · Cited by 8 · see citing works
Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity
Shakya, M., Gahlot, S., White, A. E., Verchere, C. B., Low, M. J., & Lindberg, I. (2021) · Endocrinology · doi:10.1210/endocr/bqab055 · Cited by 7 · see citing works
- Authors
- do Carmo, J. M., da Silva, A. A., Cai, Z., Lin, S., Dubinion, J. H., & Hall, J. E.
- Affiliations
- From the Departments of Physiology and Biophysics (J.M.d.C., A.A.d.S., J.H.D., J.E.H.) and Pediatrics (Z.C., S.L.), University of Mississippi Medical Center, Jackson, MS.
- University of Mississippi Medical Center (US)
- Venue
- Hypertension
- Published
- 2011-05
- Volume
- 57
- Issue
- 5
- Pages
- 918-926
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3092393
- OpenAlex
- W1975214074
- Cited by
- 127
- References
- 34
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 2 · 2021: 9 · 2020: 13 · 2019: 6 · 2018: 10 · 2017: 18 · 2016: 11 · 2015: 8 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL051971)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, leptin receptor, proopiomelanocortin neurons, melanocortin system, blood pressure regulation, appetite, glucose regulation, insulin, oxygen consumption, energy balance, metabolic syndrome, hyperleptinemia, hyperglycemia, heart rate
- MeSH terms
- Analysis of Variance, Animals, Appetite, Blood Glucose, Blood Pressure, Body Weight, Eating, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Immunohistochemistry, Insulin, Male, Motor Activity, Neurons, Oxygen Consumption, Pro-Opiomelanocortin, Telemetry, Mice, Knockout, Leptin, Mice, Receptors, Leptin
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