The hypothalamic role of BACE1 in energy homeostasis
Obesity is a global problem, with significant rises in obesity levels observed in recent years. This is owing to our modern lifestyles, associated with diminished physical activity and increased calorific intake. The increase in obesity is closely linked with type 2 diabetes mellitus (T2DM), leptin and insulin resistance, impaired glucose homeostasis and often inflammation and endoplasmic reticulum stress. Worryingly, obesity and T2DM are also risk factors for Alzheimer’s disease (AD). The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is critically involved in AD development, cleaving the amyloid precursor protein (APP) to generate amyloid-β (Aβ), which drives progression of the hallmark pathologies of AD. Consequently, higher BACE1 levels/activity is considered a primary causative factor for AD. Increased BACE1 is driven by chronic stress (e.g. hypoxia, oxidative and metabolic) also associated with obesity and T2DM. Thus, impaired glucose homeostasis and insulin resistance is common to all three disease states, suggesting that BACE1 and Aβ may contribute to the progression of metabolic disease. Consequently, BACE1 knock-out mice have been demonstrated to be protected against diet-induced obesity (DIO) and have improved insulin and leptin sensitivity. Here we show that pharmacological inhibition of BACE1 improves metabolic syndrome in mice, and that elevations in BACE1, through altered APP processing, may exacerbate obesity and the metabolic syndrome. Furthermore, we show that BACE1 is present in hypothalamic nuclei and neuronal populations that control energy balance. Taken together, these data suggest BACE1 activity alters energy metabolism through actions on the neuronal circuitry regulating energy balance, and chronically raised BACE1 levels/activity may result in dysregulation of these circuits and consequent metabolic disorder. Accordingly, a better understanding of the role of APP processing and BACE1 activity under physiological and pathophysiological conditions may provide evidence for repurposing BACE1 inhibitors, currently in clinical trials for AD, towards treatment of obesity and T2DM.
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