A Mathematical Model of Murine Metabolic Regulation by Leptin: Energy Balance and Defense of a Stable Body Weight
Open accessAbstract
We have developed a physiologically based mathematical model, with parameters derived from published experimental data, to simulate the regulatory effects of the leptin pathway on murine energy homeostasis. Model outcomes are consistent with data reported in the literature and reproduce key characteristics of the energy regulatory system, including compensatory responses that counteract changes in body weight and the failure of this ability when the leptin pathway is disrupted. Our model revealed the possibility of multiple steady states for body weight. It also provided a unified theoretical framework for two historically antagonistic hypotheses regarding body weight regulation ("set-point" versus "settling point"). Finally, our model has identified potential avenues for future investigations.
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The integrated systems by which the brain and body communicate to regulate body weight may indicate single or multiple set-points for weight that may be difficult to adjust.
“The integrated systems by which the brain and body communicate to regulate body weight may indicate single or multiple set-points for weight that may be difficult to adjust 12,19–21.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [20]
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Cites
Role of leptin in the neuroendocrine response to fasting
Ahima, R. S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., & Flier, J. S. (1996) · Nature · doi:10.1038/382250a0 · Cited by 3,117 · see citing works
Central nervous system control of food intake and body weight
Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S., & Schwartz, M. W. (2006) · Nature · doi:10.1038/nature05026 · Cited by 2,503 · see citing works
Obesity and the regulation of energy balance
Spiegelman, B. M., & Flier, J. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00240-9 · Cited by 2,398 · see citing works
Changes in Energy Expenditure Resulting from Altered Body Weight
Leibel, R. L., Rosenbaum, M., & Hirsch, J. (1995) · New England Journal of Medicine · doi:10.1056/nejm199503093321001 · Cited by 2,012 · see citing works
The role of depot fat in the hypothalamic control of food intake in the rat
Gc, K. (1953) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1953.0009 · Cited by 1,432 · see citing works
Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding
Bouret, S. G., Draper, S. J., & Simerly, R. B. (2004) · Science · doi:10.1126/science.1095004 · Cited by 1,219 · see citing works
Mechanisms of leptin action and leptin resistance.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100707 · Cited by 1,074 · see citing works
Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans
Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J., & Porte, D. (1996) · Nature Medicine · doi:10.1038/nm0596-589 · Cited by 1,014 · see citing works
Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin
Pinto, S., Roseberry, A. G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J. M., & Horvath, T. L. (2004) · Science · doi:10.1126/science.1089459 · Cited by 987 · see citing works
Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjørbæk, C., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9842 · Cited by 887 · see citing works
Stice, E., Spoor, S., Bohon, C., & Small, D. M. (2008) · Science · doi:10.1126/science.1161550 · Cited by 786 · see citing works
Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
van Heek, M., Compton, D. S., France, C. F., Tedesco, R. P., Fawzi, A. B., Graziano, M. P., Sybertz, E. J., Strader, C. D., & Davis, H. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119171 · Cited by 752 · see citing works
Dietary obesity in nine inbred mouse strains
West, D. B., Boozer, C. N., Moody, D. L., & Atkinson, R. L. (1992) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1992.262.6.r1025 · Cited by 492 · see citing works
Collins, S., Martin, T. L., Surwit, R. S., & Robidoux, J. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.02.006 · Cited by 486 · see citing works
Impaired transport of leptin across the blood-brain barrier in obesity☆
Banks, W. A., DiPalma, C., & Farrell, C. L. (1999) · Peptides · doi:10.1016/s0196-9781(99)00139-4 · Cited by 334 · see citing works
The adipocyte as an active participant in energy balance and metabolism
Badman, M. K., & Flier, J. S. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.058 · Cited by 256 · see citing works
Levin, B. E. (2006) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2006.1851 · Cited by 222 · see citing works
Reversal of diet-induced obesity and diabetes in C57BL/6J mice
Parekh, P. I., Petro, A. E., Tiller, J. M., Feinglos, M. N., & Surwit, R. S. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90283-9 · Cited by 197 · see citing works
Leptin Rapidly Lowers Food Intake and Elevates Metabolic Rates in Lean and ob/ob Mice ,
Mistry, A. M., Swick, A. G., & Romsos, D. R. (1997) · The Journal of Nutrition · doi:10.1093/jn/127.10.2065 · Cited by 188 · see citing works
Set points, settling points, and the control of body weight☆
Wirtshafter, D., & DAVIS, J. (1977) · Physiology & Behavior · doi:10.1016/0031-9384(77)90162-7 · Cited by 182 · see citing works
Banks, W. A., Clever, C. M., & Farrell, C. L. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.6.e1158 · Cited by 168 · see citing works
The non-regulation of food intake in humans: Hope for reversing the epidemic of obesity
Levitsky, D. A. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.08.053 · Cited by 163 · see citing works
Appetite and the regulation of body composition
Weigle, D. S. (1994) · The FASEB Journal · doi:10.1096/fasebj.8.3.8143936 · Cited by 155 · see citing works
Computational model of in vivo human energy metabolism during semistarvation and refeeding
Hall, K. D. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00523.2005 · Cited by 134 · see citing works
Fetissov, S. O., Meguid, M. M., Sato, T., & Zhang, L.-H. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00092.2002 · Cited by 119 · see citing works
Mode of action of OB protein (leptin) on feeding
Flynn, M. C., Scott, T. R., Pritchard, T. C., & Plata‐Saláman, C. R. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.1.r174 · Cited by 119 · see citing works
Forty mouse strain survey of body composition
Reed, D. R., Bachmanov, A. A., & Tordoff, M. G. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.03.026 · Cited by 117 · see citing works
Caloric regulation of food intake in man.
Spiegel, T. A. (1973) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0035006 · Cited by 108 · see citing works
CO2 Output and Energy Balance of Hereditary Obese Mice
McClintock, R., & Lifson, N. (1957) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1957.189.3.463 · Cited by 107 · see citing works
Heterozygosity forLepoborLeprdbaffects body composition and leptin homeostasis in adult mice
Chung, W. K., Belfi, K., Chua, M., Wiley, J., Mackintosh, R. M., Nicolson, M. A., Boozer, C. N., & Leibel, R. L. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.274.4.r985 · Cited by 105 · see citing works
On Raising Energy Expenditure in ob/ob Mice
Himms‐Hagen, J. (1997) · Science · doi:10.1126/science.276.5315.1132 · Cited by 86 · see citing works
Core temperature, O2 consumption, and early detection of ob-ob genotype in mice
Kaplan, M. L., & Leveille, G. A. (1974) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1974.227.4.912 · Cited by 69 · see citing works
Factors promoting and ameliorating the development of obesity
Levin, B. E. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.08.054 · Cited by 69 · see citing works
Exercise and Diet in Obesity Treatment: An Integrative System Dynamics Perspective
Abdel‐Hamid, T. K. (2003) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000053659.32126.2d · Cited by 41 · see citing works
Body Weight Setpoint, Metabolic Adaption and Human Starvation
Kozusko, F. (2001) · Bulletin of Mathematical Biology · doi:10.1006/bulm.2001.0229 · Cited by 40 · see citing works
Dietary control of food intake in cats
Hirsch, E. S., Dubose, C., & Jacobs, H. L. (1978) · Physiology & Behavior · doi:10.1016/0031-9384(78)90222-6 · Cited by 35 · see citing works
Rafael, J., & Herling, A. W. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.278.3.r790 · Cited by 29 · see citing works
A model for the dynamics of human weight cycling
Goldbeter, A. (2006) · Journal of Biosciences · doi:10.1007/bf02705242 · Cited by 23 · see citing works
Dilution of the Diet and Feed Intake in the Mouse
Dalton, D. C. (1965) · Nature · doi:10.1038/205807a0 · Cited by 12 · see citing works
Effects of periodic intake of a high-caloric diet on body mass and leptin resistance
Díaz, M. B., Eiden, S., Daniel, C., et al. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.03.028 · Cited by 10 · see citing works
Measurement of ‘Basal’ and Total Metabolism in Hereditarily Obese-Hyperglycemic Mice
McClintock, R., & Lifson, N. (1958) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1958.193.3.495 · Cited by 8 · see citing works
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- Fogler HS 1999 Elements of Chemical Reaction Engineering 3rd Upper Saddle River New Jersey Prentice Hall
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Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
Brown fat as a therapy for obesity and diabetes
Cypess, A. M., & Kahn, C. R. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328337a81f · Cited by 376 · see citing works
Polidori, D., Sanghvi, A., Seeley, R. J., & Hall, K. D. (2016) · Obesity · doi:10.1002/oby.21653 · Cited by 209 · see citing works
Wiebe, N., Padwal, R., Field, C., Marks, S., Jacobs, R., & Tonelli, M. (2011) · BMC Medicine · doi:10.1186/1741-7015-9-123 · Cited by 118 · see citing works
Obesity and Cancer: An Angiogenic and Inflammatory Link
Fukumura, D., Incio, J., Shankaraiah, R. C., & Jain, R. K. (2016) · Microcirculation · doi:10.1111/micc.12270 · Cited by 69 · see citing works
Self-citationSparse System Identification of Leptin Dynamics in Women With Obesity
Amin, M. R., Pednekar, D. D., Azgomi, H. F., van Wietmarschen, H., Aschbacher, K., & Faghih, R. T. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.769951 · Cited by 14 · see citing works
- Authors
- Tam, J., Fukumura, D., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Jain, Rakesh K.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 9
- Issue
- 1
- Pages
- 52-63
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2643084
- OpenAlex
- W1506352960
- Cited by
- 52
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2020: 1 · 2019: 1 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 1 · 2012: 3
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- Elsevier eBooks
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA115767, CA-85140, CA115767, CA-80124, R01CA085140, R01CA096915, R24CA085140, P01CA080124, CA96915)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, energy homeostasis, body weight regulation, compensatory growth, multiple steady states
- MeSH terms
- Algorithms, Animals, Body Weight, Energy Metabolism, Male, Mice, Inbred C57BL, Models, Biological, Obesity, Mice, Knockout, Leptin, Mice
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