Targeting the aspartic protease BACE1 for inhibition in order to increase hypothalamic leptin sensitivity and reverse obesity.

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Chronic obesity is currently at epidemic levels in the UK and many other countries worldwide and is having a major adverse impact on our society. It is estimated that more 25% of the adult population are obese and around two thirds are either overweight or obese. Worryingly over the last 20 years there has been a ~3 fold increase in the number of children and adolescents who are obese or overweight. This trend is alarming, as chronic obesity is associated with increased risk of a number of diseases such as diabetes, cardiovascular disease, Alzheimer's and a number of cancers. It is clear that our society is on a trajectory that will see significant increases in the proportion of individuals entering or in old age with severe chronic health issues. This places an enormous burden on the NHS and society generally, which is likely to worsen over the next 10-20 years if effective actions are not taken soon.The hormone, leptin, plays an important role in the maintenance of long term body weight and fat levels in animals and humans, It acts in the brain, in an area called the hypothalamus, to decrease feeding and increase energy expenditure. However, leptin's effects on appetite and energy expenditure are diminished in aged and obese individuals, despite increased circulating levels of the hormone. This phenomenon is known as leptin resistance and is thought to be due to reduced transport of leptin into the brain and/or a loss of the ability of leptin to alter the function of cells in the hypothalamus. Thus in non-obese individuals leptin alters the amount of certain neurotransmitters within neurons, their release onto nearby cells and their actions on these cells. These effects are lost or diminished through diet-induced obesity in both humans and animal models of obesity. Presently there are few effective drug treatments for obesity and none that overcome leptin resistance in the hypothalamus. The enzyme, BACE1 cuts a larger protein known as amyloid precursor protein resulting in smaller protein fragments, some of which are thought to be toxic and responsible for the pathology associated with Alzheimer's Disease (AD). Indeed, excessive activity of BACE1 in the brain is thought to be the primary driver for the neurodegeneration and cognitive dysfunction associated with AD. The amount and activity of BACE1 increases with age and following pathological stresses such as hypoxia, oxidative stress (e.g. free radicals) and physical brain injury, thus increasing the risk of AD. Features common to AD and to diabetes and obesity are the loss of function of important metabolic hormones such as insulin and leptin and the reduced ability of cells to take up and use glucose. Consequently, we hypothesised that BACE1 plays an important role that connects cell stresses (metabolic, oxidative and inflammatory) with glucose and fat metabolism. To date our work has shown that removing or decreasing BACE1 in mice causes them to be lean, resistant to weight (fat) gain on a high fat (calorie) diet and to improve their ability to deal with increased amounts of glucose in the blood (as occurs after a meal). In other words, these mice appear resistant to obesity and diabetes normally induced by chronic excess caloric intake. In a pilot study we show that by reducing the amount of BACE1, leptin is more effective in the hypothalamus and remains so even when animals become obese (i.e obesity is reversible by increasing the amount of leptin in the blood). This information suggests that reducing BACE1 prevents or reverses leptin resistance. Importantly our recent experiments show that giving obese mice (which are resistant to endogenous leptin) a drug that inhibits BACE1 causes significant weight loss. We now wish to confirm and extend these preliminary findings by studying a larger number of animals made obese by high fat diet and to try to define what has changed in the hypothalamus to circumvent leptin resistance.