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

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.

Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat

“…There are also concerns about potential on-target side effects of BACE1 inhibition due to the large number of BACE1 substrates that the enzyme is believed to cleave (Hemming et al 2009;Kuhn et al 2012). While numerous investigators have described BACE1 knockout (KO) mice as being viable, fertile, and with no gross or histological abnormalities (Luo et al 2001(Luo et al , 2003Roberds et al 2001), others have reported effects on growth and mortality, adiposity, hypomyelination, schizophrenia-like behavior, seizures, and defects in cognition and motor coordination (Laird et al 2005;Dominguez et al 2005;Willem et al 2006;Savonenko et al 2008;Hu et al 2010;Meakin et al 2012;Cheret et al 2013). The long-term effects of pharmacological inhibition of BACE1 in animals or humans have not been reported; however, latestage clinical studies are underway.…”

Loss of bace1 in mice does not alter the severity of caerulein induced pancreatitis

“…In addition, BACE1 finsertms to play a role in glucose and lipid homoeostasis and may be a link between Alzheimer's disease and diabetes [19,20]. Besides its well-characterized expression pattern in the brain, BACE1 mRNA was also detected in non-neuronal tissue, especially within the pancreas [21,22].…”

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

“…203 Pharmacological reduction of BACE1 activity by Merck-3 inhibitor in a skeletal muscle cell line also increased insulin signaling and glucose uptake. 203 These results suggest a role for BACE1 in glucose homoeostasis, which is further supported by proteomics studies. 101 As type 2 diabetes is being proposed as a possible risk factor for AD, 204 determining if BACE1 inhibition may help fight insulin resistance and decrease blood glucose levels would require future interest.…”

“…Interestingly, the close observation of BACE1 -/-mice showed a reduction in body weight, with increased energy expenditure and reduced metabolic efficiency, as well as increased glucose disposal and insulin sensitivity. 203 These mice are also protected against high fat diet-induced obesity. 203 Pharmacological reduction of BACE1 activity by Merck-3 inhibitor in a skeletal muscle cell line also increased insulin signaling and glucose uptake.…”

“…203 These mice are also protected against high fat diet-induced obesity. 203 Pharmacological reduction of BACE1 activity by Merck-3 inhibitor in a skeletal muscle cell line also increased insulin signaling and glucose uptake. 203 These results suggest a role for BACE1 in glucose homoeostasis, which is further supported by proteomics studies.…”