Abstract
Obesity and Type II Diabetes Mellitus (T2DM) are two of the most prevalent medical conditions in modern society, associated with increased energy intake and diminished physical activity. Obesity and T2DM correlate with several physiological perturbations, including impaired glucose homeostasis, increased inflammation and other conditions such as Alzheimer’s disease (AD). These factors, accompanied with an ageing population, has generated a need to produce novel therapeutics that could prevent or delay the onset of these conditions.One of the leading hypotheses as to the mechanism behind the neuronal death associated with AD is the production of amyloid beta (Aβ) peptides, which ultimately form plaques and are present in AD brains when examined post-mortem. The rate limiting step in the production of these peptides is the cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1). BACE1 is an aspartyl protease which is up-regulated by a number of cellular stresses, including hypoxia and metabolic stress, such as with high fat diet (HFD). This led to the suggestion that BACE1 may play a role in energy homeostasis. Consequently, the lab found that global knock-out of BACE1 protects mice from diet induced obesity (DIO), with accompanying improvements in glucose homeostasis, leptin sensitivity, alongside reduced inflammation. Furthermore, central infusion of Aβ peptides worsened glucose homeostasis and increased body weight in mice on a high fat diet (HFD). These data suggested that APP processing plays an important role in energy homeostasis, but it remained unclear as to whether these effects were centrally or peripherally mediated.
This thesis sought to address these questions. Mice with BACE1 removed from adipocytes are protected from DIO, with improvements in glucose homeostasis, without substantial changes in adipose tissue inflammatory status. Furthermore, peripheral infusion of Aβ peptides did not replicate the central infusion experiments. These data suggest that adipocyte BACE1 plays a vital role in modulating peripheral energy homeostasis, but that this is likely to be via BACE1 substrates than other APP, further implying that BACE1 inhibitor drugs could be repurposed to treat obesity and associated pathologies.
| Date of Award | 2018 |
|---|---|
| Original language | English |
| Sponsors | Medical Research Council |
| Supervisor | Michael Ashford (Supervisor), Calum Sutherland (Supervisor) & John Hayes (Supervisor) |