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Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome
Open accessAbstract
Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts.
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“The SNS increases in response to caloric surplus, with norepinephrine activating β-adrenergic receptors, particularly in BAT. This stimulates UCP1 in BAT mitochondria, generating heat through uncoupled respiration.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [39]
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“We showed for the first time that norepinephrine, the main neurotransmitter of SNS, upregulates the expression of SGLT2 protein in human proximal renal tubular cells [54].”
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“In humans, chronic activation of the SNS has been reported in patients with obesity, metabolic syndrome, and type 2 diabetes [48,49].”
BackgroundWang, X., Ren, J., Ren, H., Song, W., Qiao, Y., Zhao, Y., Linghu, L., Cui, Y. Y., Zhao, Z., Chen, L., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-40036-5 · Cited by 48
Carotid body chemosensitivity: early biomarker of dysmetabolism in humans
Cunha-Guimaraes, J. P., Guarino, M. P., Timóteo, A. T., Caires, I., Sacramento, J. F., Ribeiro, M. J., Selas, M., Santiago, J. C. P., Carmo, M. M., & Conde, S. V. (2020) · European Journal of Endocrinology · doi:10.1530/eje-19-0976 · Cited by 45
The role of metabolic syndrome in sudden cardiac death risk: Recent evidence and future directions
Tirandi, A., Carbone, F., Montecucco, F., & Liberale, L. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13693 · Cited by 48
Thiesse, L., Rudzik, F., Spiegel, K., Leproult, R., Pieren, R., Wunderli, J. M., Foraster, M., Héritier, H., Eze, I. C., Meyer, M., et al. (2018) · Environment International · doi:10.1016/j.envint.2018.05.036 · Cited by 43
“, 1996), or increased sympathetic nervous activity and catecholamine levels (Lembo et al., 1994; Thorp and Schlaich, 2015), are Fig.”
BackgroundTheodorakis, N., Kreouzi, M., Pappas, A., & Nikolaou, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413438 · Cited by 43
Mendoza, M. F., Kachur, S. M., & Lavie, C. J. (2020) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000749 · Cited by 42
Lona, G., Hauser, C., Köchli, S., Infanger, D., Endes, K., Schmidt‐Trucksäss, A., & Hanssen, H. (2021) · Pediatric Research · doi:10.1038/s41390-020-01278-5 · Cited by 43
Oroian, B. A., Ciobica, A. S., Timofte, D. V., Ștefănescu, C., & Șerban, I. L. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5599265 · Cited by 52
“Metabolic disorders are equally correlated with a heightened SNS activity [122, 123], such as enhanced muscle sympathetic nerve activity.”
BackgroundSympathetic innervation of the mouse kidney and liver arising from prevertebral ganglia
Torres, H., Huesing, C., Burk, D. H., Molinas, A., Neuhuber, W., Berthoud, H., Münzberg, H., Derbenev, A. V., & Zsombok, A. (2021) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00079.2021 · Cited by 43
Coordinated human sleeping brainwaves map peripheral body glucose homeostasis
Vallat, R., Shah, V. D., & Walker, M. P. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101100 · Cited by 39
“One possible mechanism explaining the recognized link between deficient sleep and impaired blood glucose control is an alteration of autonomic sympathovagal balance resulting in a biased state of sympathetic activity over parasympathetic activity,(30) which may chronically lead to insulin resistance and metabolic dysf…”
BackgroundSvensson, M. K. E., Lindmark, S., Wiklund, U., Rask, P., Karlsson, M., Myrin, J., Kullberg, J., Johansson, L. O. M., & Eriksson, J. W. (2016) · Cardiovascular Diabetology · doi:10.1186/s12933-016-0411-8 · Cited by 40
“Elevated activity of the SNS has thus been proposed as a causal factor in the “insulin resistance syndrome” [7].”
BackgroundRamos, J. S., Dalleck, L. C., Borrani, F., Beetham, K. S., Mielke, G. I., Dias, K. A., Wallen, M. P., Keating, S. E., Fassett, R. G., & Coombes, J. S. (2017) · International Journal of Cardiology · doi:10.1016/j.ijcard.2017.07.063 · Cited by 38
“Moreover, impaired CAF has also been put forth as an underlying cause of MetS [4].”
BackgroundKraft, G., Vrba, A., Scott, M. F., Allen, E. J., Edgerton, D. S., Williams, P. E., Vafai, S. B., Azamian, B. R., & Cherrington, A. D. (2019) · Diabetes · doi:10.2337/db18-1209 · Cited by 38
“Elevated sympathetic nerve activity has been hypothesized to be the cornerstone linking obesity and the metabolic syndrome (17,18), but it is not clear whether sympathetic nerve overactivity is the consequence or the cause of metabolic abnormalities.”
BackgroundXiao, Y., Yin, S., Wang, J., Cui, J., Yang, Z., Wang, J., & Bai, Y. (2023) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1137191 · Cited by 37
“Compared to people without it, overactivated sympathetic activity and decreased vagal activity are more likely to be seen in people with MetS and depression (18, 23).”
BackgroundResistin, an Adipokine with Non-Generalized Actions on Sympathetic Nerve Activity
Badoer, E., Kosari, S., & Stebbing, M. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00321 · Cited by 36
Crosstalk between Schizophrenia and Metabolic Syndrome: The Role of Oxytocinergic Dysfunction
Goh, K. K., Chen, C. Y.-A., Wu, T., Chen, C.-H., & Lu, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137092 · Cited by 41
“Preceding autonomic nervous system dysfunction in persons with metabolic syndrome [306] as well as in those with schizophrenia [307] is another neurobiological factor that is common to schizophrenia and metabolic syndrome.”
BackgroundA systematic review and meta-analysis of heart rate variability in COPD
Alqahtani, J. S., Aldhahir, A. M., Alghamdi, S. M., Ghamdi, S. S. A., AlDraiwiesh, I. A., Alsulayyim, A. S., Alqahtani, A., Alobaidi, N. Y., Saikhan, L. A., AlRabeeah, S. M., et al. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1070327 · Cited by 36
“Interestingly, common chronic diseases such as cancer (44), obesity and metabolic syndrome (45), heart failure (46), cirrhosis (47), smoking (48), and hypertension (49), are associated with an activation of sympathetic and a decrease in parasympathetic nervous activity.”
BackgroundSohn, R. E., & Jenei‐Lanzl, Z. (2023) · NeuroImmunoModulation · doi:10.1159/000531798 · Cited by 37
“All the above-mentioned OA comorbidities have one major characteristic in common: they all involve SNS over-activity resulting in chronic low-grade in-fl ammation [169, 176 – 182].”
BackgroundObesity and hypertension: Obesity medicine association (OMA) clinical practice statement (CPS) 2023
Clayton, T. L., Fitch, A., & Bays, H. E. (2023) · Obesity Pillars · doi:10.1016/j.obpill.2023.100083 · Cited by 39
“…distention, which, along with effects upon autonomic nervous and baroreflex systems, can cause relative or absolute reduction in blood pressure (postprandial hypotension), increased heart rate (commonly detected by wearable heart rate technology after meals), and sometimes lightheadedness [24,26].”
BackgroundInfluentialType 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm
Bar‐Tana, J. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09545-w · Cited by 38
Estato, V., do Nascimento, A. R., Antunes, B., Gomes, F., Coelho, L. L., Silvares, R. R., Garzoni, L. R., Daliry, A., Bousquet, P., & Tibiriçá, E. V. (2016) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2016.0085 · Cited by 34
Wu, Q., Zhao, M. F., He, X., Xue, R., Li, D., Yu, X., Wang, S., & Zang, W. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1965734 · Cited by 34
Han, G., Yang, H., Bahry, M. A., Tran, P. V., Do, P. H., Ikeda, H., Furuse, M., & Chowdhury, V. S. (2016) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2016.10.013 · Cited by 34
Melo, B. F., Sacramento, J. F., Ribeiro, M. J., Prego, C. S., Correia, M., Coelho, J. C., Cunha-Guimaraes, J. P., Rodrigues, T., Martins, I. B., Guarino, M. P., et al. (2019) · Nutrients · doi:10.3390/nu11061197 · Cited by 36
“It is our view that the widespread use of this model should be questioned, given that: (1) The Zucker diabetic rat lacks functional leptin receptors (fa/fa genotype), because leptin receptor deficiency is infrequently seen in obese and T2D humans since leptin receptor mutations are relatively rare [28]; (2) we have sh…”
Sacramento, J. F., Martins, F. O., Rodrigues, T., Matafome, P. N., Ribeiro, M. J., Olea, E., & Conde, S. V. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00262 · Cited by 34
“There is accumulating evidences from animal and human studies showing that central sympathetic overactivity plays a pivotal role in the etiology and complications of insulin resistance (31, 32).”
BackgroundPellegata, N. S., Berriel Diaz, M., Rohm, M., & Herzig, S. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10058-y · Cited by 33
Influences of lifestyle factors on cardiac autonomic nervous system activity over time
Hu, M. X., Lamers, F., de Geus, E. J. C., & Penninx, B. W. J. H. (2016) · Preventive Medicine · doi:10.1016/j.ypmed.2016.11.003 · Cited by 33
Cerebrovascular Disease: Consequences of Obesity-Induced Endothelial Dysfunction
Letra, L., & Sena, C. M. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-63260-5_7 · Cited by 33
Skúladóttir, G. V., Nilsson, E., Mwinyi, J., & Schiöth, H. B. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0309-1 · Cited by 32
“The precise mechanism through which the brain regulates changes in hormone release with sleep deprivation is unknown, but one possibility is increased sympathetic nervous system activity [38].”
BackgroundTian, M., Reichetzeder, C., Li, J., & Hocher, B. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002156 · Cited by 32
Decoding Neural Metabolic Markers From the Carotid Sinus Nerve in a Type 2 Diabetes Model
Cracchiolo, M., Sacramento, J. F., Mazzoni, A., Panarese, A., Carpaneto, J., Conde, S. V., & Micera, S. (2019) · IEEE Transactions on Neural Systems and Rehabilitation Engineering · doi:10.1109/tnsre.2019.2942398 · Cited by 34
“Overactivation of the sympathetic nervous system (SNS) is an autonomic dysfunction associated with hypertension (HT) as well to insulin resistance (IR) and glucose intolerance, typical features of type 2 diabetes mellitus [1]–[4].”
BackgroundSacramento, J. F., Andrzejewski, K., Melo, B. F., Ribeiro, M. J., Obeso, A., & Conde, S. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155545 · Cited by 35
“The sympathetic nervous system is known to play a role in the generation of metabolic diseases [3,4] and several factors have been postulated to be responsible for this increased sympathetic activation, such as hyperinsulinemia, hyperleptinemia,”
BackgroundExploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth
Bizerea, T. O., Pitulice, L., Bizerea-Spiridon, O., & Moga, T. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137276 · Cited by 34
“Activation of the sympathetic nervous system regulating the stress response, various mental health conditions, etc. [67–71].”
BackgroundBetta, M., Handjaras, G., Ricciardi, E., Pietrini, P., Haba‐Rubio, J., Siclari, F., Heinzer, R. C., & Bernardi, G. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2019.12.030 · Cited by 30
Androgens and Blood Pressure Control
Reckelhoff, J. F. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.11.016 · Cited by 31
Metadata
- Authors
- Thorp, A. A., & Schlaich, M. P.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Corresponding author
- Schlaich, Markus P.
- ORCID
- Schlaich, Markus P.
- Venue
- Journal of Diabetes Research
- Publisher
- Wiley
- Published
- 2015
- Volume
- 2015
- Pages
- 1-11
- ISSN
- 2314-6745 (ISSN-L)
- 2314-6753
- PMC
- PMC4430650
- OpenAlex
- W2066041574
- Cited by
- 425
- References
- 101
- Citations by year
- 2026: 28 · 2025: 42 · 2024: 36 · 2023: 44 · 2022: 40 · 2021: 45 · 2020: 48 · 2019: 40 · 2018: 33 · 2017: 31 · 2016: 32 · 2015: 5
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Diabetes Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Health and Medical Research Council
- Victorian Government’s Operational Infrastructure Support Program
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- sympathetic nervous system, sympathetic hyperactivity, obesity, metabolic syndrome, energy homeostasis, abdominal obesity, insulin resistance, baroreflex sensitivity, hyperinsulinemia, adipokines, type 2 diabetes, cardiovascular disease, sympathetic activity, device therapy
- MeSH terms
- Animals, Humans, Obesity, Sympathetic Nervous System, Metabolic Syndrome
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