The gut-derived
hormone, peptide YY (PYY) reduces food intake and enhances satiety in both humans and animals. Obese individuals also have a deficiency in circulating
peptide YY, although whether this is a cause or a consequence of
obesity is unclear. Our aims were to determine whether
peptide YY (PYY) over-expression may have
therapeutic effects for the treatment of
obesity by altering energy balance and
glucose homeostasis. We generated PYY transgenic mice and measured
body weight, food intake, temperature, adiposity,
glucose tolerance, circulating
hormone and
lipid concentrations and hypothalamic
neuropeptide levels (
neuropeptide Y;
proopiomelanocortin, and
thyrotropin-releasing hormone) under chow and high-fat feeding and after crossing these mice onto the genetically obese
leptin-deficient ob/ob mouse background. PYY transgenic mice were protected against diet-induced
obesity in association with increased body temperature (indicative of increased thermogenesis) and sustained expression of
thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus. Moreover, PYY transgenic mice crossed onto the genetically obese ob/ob background had significantly decreased
weight gain and adiposity, reduced serum
triglyceride levels and improved
glucose tolerance compared to ob/ob controls. There was no effect of PYY transgenic over expression on basal or fasting-induced food intake measured at 11-12 weeks of age. Together, these findings suggest that long-term administration of PYY, PYY-like compounds or agents that stimulate PYY synthesis in vivo can reduce excess adiposity and improve
glucose tolerance, possibly via effects on the hypothalamo-pituitary-thyroid axis and thermogenesis.