Leptin mediates the increase in blood pressure associated with obesity

Stephanie E. Simonds; Jack T. Pryor; Eric Ravussin; Frank L. Greenway; Ralph Dileone; Andrew M. Allen; Jaspreet Bassi; Joel K. Elmquist; Julia M. Keogh; Elana Henning; Martin G. Myers; Julio Licinio; Russell D. Brown; Pablo J. Enriori; Stephen O'Rahilly; Scott M. Sternson; Kevin L. Grove; David C. Spanswick; I. Sadaf Farooqi; Michael A. Cowley

doi:10.1016/j.cell.2014.10.058

Leptin mediates the increase in blood pressure associated with obesity

Stephanie E. Simonds, Jack T. Pryor, Eric Ravussin, Frank L. Greenway, Ralph Dileone, Andrew M. Allen, Jaspreet Bassi, Joel K. Elmquist, Julia M. Keogh, Elana Henning, Martin G. Myers, Julio Licinio, Russell D. Brown, Pablo J. Enriori, Stephen O'Rahilly, Scott M. Sternson, Kevin L. Grove, David C. Spanswick, I. Sadaf Farooqi, Michael A. Cowley

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249 Scopus citations

Abstract

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

Original language	English (US)
Pages (from-to)	1404-1416
Number of pages	13
Journal	Cell
Volume	159
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2014.10.058
State	Published - Dec 4 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2014.10.058

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Simonds, S. E., Pryor, J. T., Ravussin, E., Greenway, F. L., Dileone, R., Allen, A. M., Bassi, J., Elmquist, J. K., Keogh, J. M., Henning, E., Myers, M. G., Licinio, J., Brown, R. D., Enriori, P. J., O'Rahilly, S., Sternson, S. M., Grove, K. L., Spanswick, D. C., Farooqi, I. S., & Cowley, M. A. (2014). Leptin mediates the increase in blood pressure associated with obesity. Cell, 159(6), 1404-1416. https://doi.org/10.1016/j.cell.2014.10.058

Simonds, SE, Pryor, JT, Ravussin, E, Greenway, FL, Dileone, R, Allen, AM, Bassi, J, Elmquist, JK, Keogh, JM, Henning, E, Myers, MG, Licinio, J, Brown, RD, Enriori, PJ, O'Rahilly, S, Sternson, SM, Grove, KL, Spanswick, DC, Farooqi, IS & Cowley, MA 2014, 'Leptin mediates the increase in blood pressure associated with obesity', Cell, vol. 159, no. 6, pp. 1404-1416. https://doi.org/10.1016/j.cell.2014.10.058

@article{36ee38c1fa51489b94c784e063f0dd00,

title = "Leptin mediates the increase in blood pressure associated with obesity",

abstract = "Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.",

author = "Simonds, {Stephanie E.} and Pryor, {Jack T.} and Eric Ravussin and Greenway, {Frank L.} and Ralph Dileone and Allen, {Andrew M.} and Jaspreet Bassi and Elmquist, {Joel K.} and Keogh, {Julia M.} and Elana Henning and Myers, {Martin G.} and Julio Licinio and Brown, {Russell D.} and Enriori, {Pablo J.} and Stephen O'Rahilly and Sternson, {Scott M.} and Grove, {Kevin L.} and Spanswick, {David C.} and Farooqi, {I. Sadaf} and Cowley, {Michael A.}",

note = "Funding Information: This work was supported by the Heart Foundation of Australia (M.A.C. and S.E.S.), the National Health and Medical Research Council of Australia (1029188 to M.A.C. and 1063955 to D.C.S.), Monash University (S.E.S.), Pfizer Australia (M.A.C.), a NORC Center grant (P30DK072476) at the Pennington Biomedical Research Center (E.R., F.L.G., and J.L.), the Leverhulme Trust (J.T.P.), the Wellcome Trust (082390/Z/07/Z) (I.S.F.), Medical Research Council (I.S.F.), NIHR Cambridge Biomedical Research Centre (I.S.F. and S.O.R.), and the Bernard Wolfe Health Neuroscience Fund (I.S.F.). We thank Professor Streamson Chua for the LepR flox mice. J.L. and I.S.F. treat patients with recombinant human leptin which is provided by BMS/AstraZeneca. Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

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doi = "10.1016/j.cell.2014.10.058",

language = "English (US)",

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T1 - Leptin mediates the increase in blood pressure associated with obesity

AU - Simonds, Stephanie E.

AU - Pryor, Jack T.

AU - Ravussin, Eric

AU - Greenway, Frank L.

AU - Dileone, Ralph

AU - Allen, Andrew M.

AU - Bassi, Jaspreet

AU - Elmquist, Joel K.

AU - Keogh, Julia M.

AU - Henning, Elana

AU - Myers, Martin G.

AU - Licinio, Julio

AU - Brown, Russell D.

AU - Enriori, Pablo J.

AU - O'Rahilly, Stephen

AU - Sternson, Scott M.

AU - Grove, Kevin L.

AU - Spanswick, David C.

AU - Farooqi, I. Sadaf

AU - Cowley, Michael A.

N1 - Funding Information: This work was supported by the Heart Foundation of Australia (M.A.C. and S.E.S.), the National Health and Medical Research Council of Australia (1029188 to M.A.C. and 1063955 to D.C.S.), Monash University (S.E.S.), Pfizer Australia (M.A.C.), a NORC Center grant (P30DK072476) at the Pennington Biomedical Research Center (E.R., F.L.G., and J.L.), the Leverhulme Trust (J.T.P.), the Wellcome Trust (082390/Z/07/Z) (I.S.F.), Medical Research Council (I.S.F.), NIHR Cambridge Biomedical Research Centre (I.S.F. and S.O.R.), and the Bernard Wolfe Health Neuroscience Fund (I.S.F.). We thank Professor Streamson Chua for the LepR flox mice. J.L. and I.S.F. treat patients with recombinant human leptin which is provided by BMS/AstraZeneca. Publisher Copyright: © 2014 The Authors.

PY - 2014/12/4

Y1 - 2014/12/4

N2 - Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

AB - Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

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Leptin mediates the increase in blood pressure associated with obesity

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