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

Meakin, Paul J., Jalicy, Susan M., Montagut, Gemma, Allsop, David J. P., Cavellini, Daniella L., Irvine, Stuart W., McGinley, Christopher, Liddell, Mary K., McNeilly, Alison D., Parmionova, Karolina, Liu, Yu-Ru, Bailey, Charlotte L. S., Dale, J. Kim, Heisler, Lora K., McCrimmon, Rory J., Ashford, Michael L. J.·2018·Scientific Reports
DOI 10.1038/s41598-017-18388-6PMC PMC5758523
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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 Aβ 1–42 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 Aβ 1–42 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 Aβ 1–42 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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  • BACE1 has been implicated in a range of metabolic functions.

    “and BACE1 has been implicated in a range of metabolic functions.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [19]

  • The influence of BACE1 on insulin signaling is in part through negative regulators PTEN and PTP1B, which are found to decrease in response to BACE1 inhibition.

    “The influence of BACE1 on insulin signaling is in part through negative regulators PTEN and PTP1B, which are found to decrease in response to BACE1 inhibition.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [19]

  • In addition to insulin signaling, other metabolic changes associated with BACE1 have been observed, including lowered plasma leptin and restored hypothalamic leptin sensitivity in obese mice.

    “In addition to insulin signaling, other metabolic changes associated with BACE1 have been observed, including lowered plasma leptin and restored hypothalamic leptin sensitivity in obese mice.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [19]

  • Inhibition of BACE1 in DIO mice normalized the STAT3 response, alongside improving glucose homeostasis, reducing hypothalamic inflammation, and normalizing hypothalamic leptin sensitivity via NPY, AgRP, and POMC signaling.

    “Inhibition of BACE1 in diet‐induced obese (DIO) mice normalized the STAT3 response, alongside improving glucose homeostasis, reducing hypothalamic inflammation, and normalizing hypothalamic leptin sensitivity via NPY, AgRP, and POMC signaling.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [19]

  • Body weight changes in BACE1 knockout and inhibitor-treated mice are likely through increased energy expenditure.

    “suggesting body weight changes are likely through increased energy expenditure.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [19]

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Research works printed but not linked: 33

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Metadata

Authors
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.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-01-08
Volume
8
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-017-18388-6
PMC
PMC5758523
Cited by
36
References
6
Language
en
Licence

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