BACE 1 Knockout Mice and BACE 1 inhibition

BACE 1 Knockout Mice and BACE 1 inhibition in Mouse models of obesity/diabetes Stuart Irvine

Obesity & Type II Diabetes • The problem http: //www. dh. gov. uk/health/2012/04/obesityfacts/

Leptin X From the following article: Leptin and the regulation of body weight in mammals Jeffrey M. Friedman and Jeffrey L. Halaas Nature 395, 763 -770(22 October 1998)

Beta-secretase 1 (BACE 1) and Mouse Models • BACE 1 is a protease responsible for cleaving Amyloid precursor protein (APP) into Aβ. – Important in plaque formation in Alzheimer’s Disease

BACE 1 models and obesity • BACE 1 KO model 1 • High fat diet – Lean phenotype – Low leptin levels in the blood – Leptin sensitive/Low leptin levels – Insulin sensitive (nondiabetic) 1 P • BACE 1 inhibition • WT mice on a HF diet, with features of obesity, type II diabetes, leptin insensitivity etc • Using BACE 1 inhibitor, mice will revert back to lean, leptin/insulinsensitive animal Meakin et al. Reduction in BACE 1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem J. 2012 January 1; 441(Pt 1): 285– 296. • Weight lost is fat (not muscle) • Leptin levels drop too

Objectives of my Project • How is knocking out BACE 1/ inhibiting BACE 1 producing a lean animal, even on a high fat diet? – Gene Expression Studies Fat Hypothalamus Muscle Leptin POMC UCP 2 UCP 1 Ag. RP UCP 3 Β-3 Adrenoceptor NPY SOCS 3