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

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...

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Published in:	Scientific reports Vol. 8; no. 1; p. 55
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 08-01-2018 Nature Publishing Group
Subjects:	14 14/19 38 38/77 631/378/1488/1562 631/443/319/1642/393 64 64/60 96 96/1 96/21 96/31 96/95 Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Aspartic Acid Endopeptidases - genetics Aspartic Acid Endopeptidases - metabolism Body Weight Body weight gain Clinical trials Diabetes mellitus Diet, High-Fat Gene Expression Glucose - metabolism Homeostasis Humanities and Social Sciences Hypothalamus Hypothalamus - metabolism Leptin Leptin - metabolism Mice Mice, Knockout Mice, Obese multidisciplinary Neuropeptides - genetics Neuropeptides - metabolism Obesity Pyramidal Cells - metabolism Rodents Science Science (multidisciplinary) Signal Transduction β-Amyloid β-Site APP-cleaving enzyme 1
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-017-18388-6