An insatiable appetite (hyperphagia), in conjunction with a low metabolic rate, means that obesity and all of its associated health risks are common in people with Prader-Willi syndrome. Overeating is one of the main barriers to independent living I adults with Prader-Willi syndrome. Moreover, attempts to control their food intake often lead to exacerbation of behavioral problems. Appetite suppression per se is unlikely to be an effective treatment for obesity in Prader-Willi syndrome, because in order to remain weight-stable these people must eat substantially less than unaffected individuals. Thus there is an urgent need for treatments that not only reduce appetite and food intake in subjects with Prader-Willi syndrome, but also increase their reduced metabolic rate. This project will determine whether two naturally derived hormones or analogues of the, could be used to treat excessive hunger and obesity in people with Prader-Willi syndrome. These hormones, called peptide YY (PYY) and pancreatic polypeptide (PP), are naturally secreted from the gastrointestinal tract, and have been shown to reduce food intake and body weight in short-term studies. Our work will determine whether long-term administration of PYY, either alone or in combination with PP, could effectively reduce food intake and body weight in obese mice, by investigation of our genetically engineered mouse line, which produces excessive amounts of PYY. This is an important aim, because people with Prader-Willi syndrome are likely to need long-term treatments for weight management. We will also determine whether PP and / or PYY are able to increase metabolic rate, an important consideration for effective treatment of obesity in Prader-Willi syndrome.
PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice. Shi YC, Lin Z, Lau J, Zhang H, Yagi M, Kanzler I, Sainsbury A, Herzog H, Lin S. Obesity. 21:E669-78, 2013
PYY transgenic mice are protected against diet-induced and genetic obesity. Boey D, Lin S, Enriquez RF, Lee NJ, Slack K, Couzens M, Baldock PA, Herzog H, Sainsbury A. Neuropeptides. 42:19-30, 2008.
Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity. Boey D, Lin S, Karl T, Baldock P, Lee N, Enriquez R, Couzens M, Slack K, Dallmann R, Sainsbury A, Herzog. Diabetologia. 49: 1360-1370, 2006.
Amanda Sainsbury-Salis, Ph.D. and Herbert Herzog, Ph.D., Neurobiology Program
Garvan Institute of Medical Research, Australia