Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice

Paul J. Meakin; Susan M. Jalicy; Gemma Montagut; David J. P. Allsop; Daniella L. Cavellini; Stuart W. Irvine; Christopher McGinley; Mary K. Liddell; Alison D. McNeilly; Karolina Parmionova; Yu-Ru Liu; Charlotte L. S. Bailey; J. Kim Dale; Lora K. Heisler; Rory J. McCrimmon; Michael L. J. Ashford

doi:10.1038/s41598-017-18388-6

Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice

Paul J. Meakin, Susan M. Jalicy, Gemma Montagut, David J. P. Allsop, Daniella L. Cavellini, Stuart W. Irvine, Christopher McGinley, Mary K. Liddell, Alison D. McNeilly, Karolina Parmionova, Yu-Ru Liu, Charlotte L. S. Bailey, J. Kim Dale, Lora K. Heisler, Rory J. McCrimmon, Michael L. J. Ashford

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Abstract

Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer’s disease, may be useful agents for the treatment of obesity and associated diabetes.

Original language	English
Article number	55
Journal	Scientific Reports
Volume	8
DOIs	https://doi.org/10.1038/s41598-017-18388-6
Publication status	Published - 8 Jan 2018

Bibliographical note

We thank AstraZeneca for providing AZ-4217, Mark Smith (Imperial College, London) and Yuchio Yanagawa (Gunma University, Maebashi) for VGlut2-GFP and GAD67-GFP tissue, respectively. This work was funded by Medical Research Council (MR/K003291/1), Diabetes UK (12/0004458), British Heart Foundation (PG/15/44/31574) and Biotechnology and Biological Sciences Research Council CASE (with AstraZeneca) award (BB/I015663/1) to MLJA and by a grant to LKH from the Wellcome Trust (WT098012).

Keywords

hypothalamus
obesity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice
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Cite this

Meakin, P. J., Jalicy, S. M., Montagut, G., Allsop, D. J. P., Cavellini, D. L., Irvine, S. W., McGinley, C., Liddell, M. K., McNeilly, A. D., Parmionova, K., Liu, Y.-R., Bailey, C. L. S., Dale, J. K., Heisler, L. K., McCrimmon, R. J., & Ashford, M. L. J. (2018). Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Scientific Reports, 8, Article 55. https://doi.org/10.1038/s41598-017-18388-6

Meakin, PJ, Jalicy, SM, Montagut, G, Allsop, DJP, Cavellini, DL, Irvine, SW, McGinley, C, Liddell, MK, McNeilly, AD, Parmionova, K, Liu, Y-R, Bailey, CLS, Dale, JK, Heisler, LK, McCrimmon, RJ & Ashford, MLJ 2018, 'Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice', Scientific Reports, vol. 8, 55. https://doi.org/10.1038/s41598-017-18388-6

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title = "Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice",

abstract = "Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer{\textquoteright}s disease, may be useful agents for the treatment of obesity and associated diabetes.",

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author = "Meakin, {Paul J.} and Jalicy, {Susan M.} and Gemma Montagut and Allsop, {David J. P.} and Cavellini, {Daniella L.} and Irvine, {Stuart W.} and Christopher McGinley and Liddell, {Mary K.} and McNeilly, {Alison D.} and Karolina Parmionova and Yu-Ru Liu and Bailey, {Charlotte L. S.} and Dale, {J. Kim} and Heisler, {Lora K.} and McCrimmon, {Rory J.} and Ashford, {Michael L. J.}",

note = "We thank AstraZeneca for providing AZ-4217, Mark Smith (Imperial College, London) and Yuchio Yanagawa (Gunma University, Maebashi) for VGlut2-GFP and GAD67-GFP tissue, respectively. This work was funded by Medical Research Council (MR/K003291/1), Diabetes UK (12/0004458), British Heart Foundation (PG/15/44/31574) and Biotechnology and Biological Sciences Research Council CASE (with AstraZeneca) award (BB/I015663/1) to MLJA and by a grant to LKH from the Wellcome Trust (WT098012).",

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AU - Jalicy, Susan M.

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AU - Allsop, David J. P.

AU - Cavellini, Daniella L.

AU - Irvine, Stuart W.

AU - McGinley, Christopher

AU - Liddell, Mary K.

AU - McNeilly, Alison D.

AU - Parmionova, Karolina

AU - Liu, Yu-Ru

AU - Bailey, Charlotte L. S.

AU - Dale, J. Kim

AU - Heisler, Lora K.

AU - McCrimmon, Rory J.

AU - Ashford, Michael L. J.

N1 - We thank AstraZeneca for providing AZ-4217, Mark Smith (Imperial College, London) and Yuchio Yanagawa (Gunma University, Maebashi) for VGlut2-GFP and GAD67-GFP tissue, respectively. This work was funded by Medical Research Council (MR/K003291/1), Diabetes UK (12/0004458), British Heart Foundation (PG/15/44/31574) and Biotechnology and Biological Sciences Research Council CASE (with AstraZeneca) award (BB/I015663/1) to MLJA and by a grant to LKH from the Wellcome Trust (WT098012).

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N2 - Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer’s disease, may be useful agents for the treatment of obesity and associated diabetes.

AB - Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1–42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aβ1–42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aβ1–42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer’s disease, may be useful agents for the treatment of obesity and associated diabetes.

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U2 - 10.1038/s41598-017-18388-6

DO - 10.1038/s41598-017-18388-6

M3 - Article

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

M1 - 55

ER -

Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice

Abstract

Bibliographical note

Keywords

UN SDGs

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