Central nervous pathways of insulin action in the control of metabolism and food intake
Open accessAbstract
Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.
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Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution.
“Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [2]
The hypothalamus modulates food intake and whole-body metabolism.
“and modulates food intake and whole-body metabolism2”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [2]
The hypothalamus influences outflows toward the periphery.
“which in turn influences outflows toward the periphery2”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [2]
Studies have addressed brain-derived modulation of peripheral metabolism in men with normal weight and obesity.
“Using this approach, studies have addressed brain-derived modulation of peripheral metabolism in men with normal weight and obesity (for review, see Kullmann et al.2).”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as Kullmann et al.2
In affected individuals, brain insulin cannot sufficiently modulate peripheral metabolism.
“In affected individuals, brain insulin cannot sufficiently modulate peripheral metabolism2.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [2]
The brain functions in 'fine-tuning' whole-body metabolism to rapidly adapt peripheral energy fluxes to current energy availability.
“This underscores the brain’s function in ‘fine-tuning’ whole-body metabolism to rapidly adapt peripheral energy fluxes to current energy availability2.”
From Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase (2023) · cites this paper as [2]
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Self-citationWardelmann, K., Blümel, S., Rath, M., Alfine, E., Chudoba, C., Schell, M., Cai, W., Hauffe, R., Warnke, K., Flore, T., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.01.001 · Cited by 68 · see citing works
Self-citationGestational Diabetes Impairs Human Fetal Postprandial Brain Activity
Linder, K., Schleger, F., Kiefer‐Schmidt, I., Fritsche, L., Kümmel, S., Heni, M., Weiß, M., Häring, H., Preissl, H. T., & Fritsche, A. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2692 · Cited by 66 · see citing works
Self-citationHigh cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention
Tschritter, O., Preissl, H. T., Hennige, A. M., Sartorius, T., Štingl, K., Heni, M., Ketterer, C., Stefan, N., Machann, J., Schleicher, E., et al. (2011) · Diabetologia · doi:10.1007/s00125-011-2309-z · Cited by 63 · see citing works
Self-citationIntranasal Insulin Suppresses Systemic but Not Subcutaneous Lipolysis in Healthy Humans
Iwen, K. A., Scherer, T., Heni, M., Sayk, F., Wellnitz, T., Machleidt, F., Preissl, H., Häring, H.-U., Fritsche, A., Lehnert, H., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3169 · Cited by 59 · see citing works
Self-citationIntranasal Insulin Reduces Olfactory Sensitivity in Normosmic Humans
Brünner, Y. F., Benedict, C., & Freiherr, J. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2061 · Cited by 59 · see citing works
Fadel, J. R., & Reagan, L. P. (2015) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2015.12.004 · Cited by 57 · see citing works
van Opstal, A. M., Kaal, I., van den Berg‐Huysmans, A. A., Hoeksma, M. R., Blonk, C., Pijl, H., Rombouts, S. A. R. B., & van der Grond, J. (2018) · Nutrition · doi:10.1016/j.nut.2018.09.004 · Cited by 57 · see citing works
Modulation of midbrain neurocircuitry by intranasal insulin
Edwin Thanarajah, S., Iglesias, S., Kuzmanovic, B., Rigoux, L., Stephan, K. E., Brüning, J. C., & Tittgemeyer, M. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.03.050 · Cited by 55 · see citing works
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Insulin actions in the mesolimbic dopamine system
Liu, S., & Borgland, S. L. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113006 · Cited by 49 · see citing works
Yamamoto, N., Matsubara, T., Sobue, K., Tanida, M., Kasahara, R., Naruse, K., Taniura, H., Sato, T., & Suzuki, K. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07668.x · Cited by 48 · see citing works
Heni, M., Kullmann, S., Ahlqvist, E., Wagner, R. J., Machicao, F. E., Staiger, H., Häring, H.-U., Almgren, P., Groop, L., Small, D. M., et al. (2016) · Diabetologia · doi:10.1007/s00125-016-4095-0 · Cited by 46 · see citing works
Self-citationRebelos, E., Immonen, H., Bucci, M., Hannukainen, J. C., Nummenmaa, L., Honka, M., Soinio, M., Salminen, P. T. P., Ferrannini, E., Iozzo, P., et al. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13501 · Cited by 46 · see citing works
The role of insulin sensitivity and intranasally applied insulin on olfactory perception
Edwin Thanarajah, S., Hoffstall, V., Rigoux, L., Hanssen, R., Brüning, J. C., & Tittgemeyer, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-43693-7 · Cited by 46 · see citing works
Fehlert, E., Willmann, K., Fritsche, L., Linder, K., Husin, H. M., Schleger, F., Weiss, M., Kiefer‐Schmidt, I., Brucker, S. Y., Häring, H., et al. (2016) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.14474 · Cited by 43 · see citing works
Self-citationInsulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans
Heni, M., Wagner, R., Willmann, C., Jaghutriz, B. A., Vosseler, A., Kübler, C., Hund, V., Scheffler, K., Peter, A., Häring, H.-U., et al. (2020) · Neuroendocrinology · doi:10.1159/000504551 · Cited by 36 · see citing works
Self-citationOtt, V., Lehnert, H., Staub, J., Wönne, K., Jan Born, A., & Hallschmid, M. (2014) · Diabetes · doi:10.2337/db14-0931 · Cited by 35 · see citing works
Hypothalam1c Lesions And Adiposity In The Rat
Hetherington, A. W., & Ranson, S. W. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.1983.tb07169.x · Cited by 35 · see citing works
Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis
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Mansur, R. B., Fries, G. R., Subramaniapillai, M., Frangou, S., Felice, F. G. D., Rasgon, N., McEwen, B. S., Brietzke, E. M., & McIntyre, R. S. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2018.10.020 · Cited by 33 · see citing works
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Hypothalamic insulin responsiveness is associated with pancreatic insulin secretion in humans
Kullmann, S., Fritsche, A., Wagner, R. J., Schwab, S., Häring, H., Preissl, H. T., & Heni, M. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.03.036 · Cited by 31 · see citing works
Self-citationInsulin action on GABA neurons is a critical regulator of energy balance but not fertility in mice.
Evans, M. C., Rizwan, M. Z., & Anderson, G. (2014) · Endocrinology · doi:10.1210/en.2014-1412 · Cited by 28 · see citing works
The anterior medial temporal lobes: Their role in food intake and body weight regulation.
Coppin, G. (2016) · Physiology and Behavior · doi:10.1016/j.physbeh.2016.08.028 · Cited by 26 · see citing works
Effects of intranasal insulin application on the hypothalamic BOLD response to glucose ingestion
van Opstal, A. M., Akintola, A. A., van der Elst, M. J. T., Westendorp, R. G. J., Pijl, H., van Heemst, D., & van der Grond, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-13818-x · Cited by 20 · see citing works
Effects of intranasal insulin on endogenous glucose production in insulin‐resistant men
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Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes
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Insulin and Estrogen Independently and Differentially Reduce Macronutrient Intake in Healthy Men
Krug, R., Mohwinkel, L., Drotleff, B., Born, J., & Hallschmid, M. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01835 · Cited by 16 · see citing works
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Plomgaard, P., Hansen, J. S., Ingerslev, B., Clemmesen, J. O., Secher, N. H., van Hall, G., Fritsche, A., Weigert, C., Lehmann, R., Häring, H., et al. (2019) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13615 · Cited by 16 · see citing works
Self-citationHeni, M., Wagner, R. J., Kullmann, S., Preissl, H. T., & Fritsche, A. (2015) · Diabetes · doi:10.2337/db15-0209 · Cited by 8 · see citing works
Self-citationBrief communication: β-cell function influences dopamine receptor availability
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Intranasal Insulin Administration Does Not Affect LH Concentrations in Men with Diabetes
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Insulin enhances presynaptic glutamate release via opioid receptor-mediated disinhibitionPreprint
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Dimitriadis, G. D., Maratou, E., Kountouri, A., Board, M., & Lambadiari, V. (2021) · Nutrients · doi:10.3390/nu13010159 · Cited by 241 · see citing works
Trapp, S., & Brierley, D. I. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15638 · Cited by 154 · see citing works
Exercise Induces Tissue-Specific Adaptations to Enhance Cardiometabolic Health
Ashcroft, S. P., Stocks, B., Egan, B., & Zierath, J. R. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.008 · Cited by 149 · see citing works
Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites
Rhea, E. M., Banks, W. A., & Raber, J. (2022) · Biomedicines · doi:10.3390/biomedicines10071582 · Cited by 76 · see citing works
Lindbohm, J. V., Mars, N., Walker, K. A., Singh‐Manoux, A., Livingston, G., Brunner, E. J., Sipilä, P. N., Saksela, K., Ferrie, J. E., Lovering, R. C., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12419 · Cited by 70 · see citing works
Ferreira, S. T. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12959 · Cited by 59 · see citing works
Insulin action on astrocytes: From energy homeostasis to behaviour
González‐García, I., Gruber, T., & García‐Cáceres, C. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12953 · Cited by 52 · see citing works
Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase
Hummel, J., Benkendorff, C., Fritsche, L., Prystupa, K., Vosseler, A., Gancheva, S., Trenkamp, S., Birkenfeld, A. L., Preissl, H., Roden, M., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00869-w · Cited by 48 · see citing works
“In humans, insulin regulates brain activity in specific regions, including the hypothalamus 10 , which in turn influences outflows toward the periphery 2 and modulates food intake and whole-body metabolism 2 .”
InfluentialSelf-citationBrain insulin responsiveness is linked to age and peripheral insulin sensitivity
Wagner, L., Veit, R., Kübler, C., Fritsche, A., Häring, H., Birkenfeld, A. L., Heni, M., Preissl, H., & Kullmann, S. (2023) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.15094 · Cited by 22 · see citing works
Self-citationWal, A., Sahu, P. K., Wal, P., Sahu, K., Bhise, M. R., & Lodhi, D. S. (2025) · Cardiovascular & Hematological Disorders-Drug Targets · doi:10.2174/011871529x326042241031060350 · Cited by 1 · see citing works
- Authors
- Kullmann, S., Kleinridders, A., Small, D. M., Fritsche, A., Häring, H.-U., Preissl, H., & Heni, M.
- Affiliations
- Helmholtz Munich (DE)
- German Center for Diabetes Research (DE)
- Corresponding author
- Kullmann, Stephanie
- ORCID
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 8
- Issue
- 6
- Pages
- 524-534
- ISSN
- 2213-8587 (ISSN-L)
- OpenAlex
- W3027292275
- Cited by
- 233
- References
- 121
- Citations by year
- 2026: 36 · 2025: 39 · 2024: 34 · 2023: 30 · 2022: 52 · 2021: 32 · 2020: 10
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (33–7533–30–10/51/1)
- Novo Nordisk
- Boehringer Ingelheim
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- brain insulin signaling, food intake regulation, glucose metabolism, insulin sensitivity, mesocorticolimbic circuitry, dopamine, obesity, type 2 diabetes, cognitive control, endogenous glucose production
- MeSH terms
- Animals, Blood Glucose, Brain, Central Nervous System, Eating, Energy Metabolism, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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