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Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Meakin, Paul J., Harper, Alex J., Hamilton, D. Lee, Gallagher, Jennifer, McNeilly, Alison D., Burgess, Laura A., Vaanholt, Lobke M., Bannon, Kirsten A., Latcham, Judy, Hussain, Ishrut, Speakman, John R., Howlett, David R., Ashford, Michael L.J.·2012·Biochemical Journal
DOI 10.1042/bj20110512PMC PMC3242510
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Abstract

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.

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  • Tissue expression of BACE1 and plasma levels of the IRsol are higher in patients with T2D, supporting the theory that BACE1 cleavage of IR drives the disease.

    “Tissue expression of BACE1 and plasma levels of the IRsol are higher in patients with T2D, supporting the theory that BACE1 cleavage of IR drives the disease.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [4]

  • Both BACE1 knockout and inhibitor-treated mice show no change in daily food intake while presenting with decreased body weight.

    “Interestingly, both BACE1 knockout and inhibitor‐treated mice show no change in daily food intake while presenting with decreased body weight”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [4]

  • BACE1 may play a role in the mechanisms behind changes in leptin levels and sensitivity.

    “Therefore, BACE1 may play a role in the mechanisms behind changes in leptin levels and sensitivity.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [4]

  • 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 [4]

  • In vivo silencing of BACE1 was found to delay DIO induced weight gain, improve glucose tolerance, increase energy expenditure and insulin sensitivity, and elevate UCP1 expression in brown fat.

    “Furthermore, in vivo silencing of BACE1 was found to delay DIO induced weight gain, improve glucose tolerance, increase energy expenditure and insulin sensitivity, and elevate UCP1 expression in brown fat.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [4]

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Metadata

Authors
Meakin, P. J., Harper, A. J., Hamilton, D. L., Gallagher, J., McNeilly, A. D., Burgess, L. A., Vaanholt, L. M., Bannon, K. A., Latcham, J., Hussain, I., Speakman, J. R., Howlett, D. R., & Ashford, M. L. J.
Affiliations
  • Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
  • Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Harlow CM19 5AW, U.K.
  • Division of Neuroscience, University of Dundee, Medical Research Institute, Dundee DD1 9SY, Scotland, U.K.
  • Aberdeen Centre for Energy Regulation and Obesity, Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, Scotland, U.K.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2011-12-14
Volume
441
Issue
1
Pages
285-296
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20110512
PMC
PMC3242510
Cited by
103
References
10
Language
en
Licence
creativecommons.org/licenses/by-nc/2.5/ (vor, 2780 d)

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