Yau-Sheng Tsai, Ph.D.

Dissertation research performed under the direction of Nobuyo Maeda

ABSTRACT
    Peroxisome proliferator-activated receptor g (PPARg), a nuclear receptor that regulates adipocyte development and glucose homeostasis, is the molecular target of a class of insulin-sensitizing drugs. Both gain- and loss-of-function mutations in the PPARg gene are implicated in the human metabolic syndrome, a complex physiological condition in which abdominal obesity, hypertension, dyslipidemia, and diabetes co-exist in a single individual. How these conditions are affected by PPARg is not clear in vivo because phenotypes associated with PPARg mutations in humans and animal models are not straightforward. I therefore used mouse genetics to study the mechanisms by which PPARg affects the metabolic syndrome.  To establish a causative link between PPARg mutation and observed phenotypes in humans, I generated a mouse model with a clinically relevant PPARg mutation, P465L, identified in patients with the metabolic syndrome. Like humans, heterozygous mutant mice have hypertension. They also display abnormal fat distribution, although the pattern of fat distribution in mice differs from that in humans. However, unlike humans, they maintain normal insulin sensitivity. Thus, severe insulin resistance in humans with this mutation may be a consequence of altered fat distribution with preferential deposition of fat in the intra-abdominal depots. These results also provide genetic evidence for a critical role of PPARg in blood pressure regulation that is not dependent on altered insulin sensitivity.  The impact of altered PPARg levels on the metabolic state was assessed through my generation of mice with quantitative PPARg variants. By changing PPAR? 3'-UTR, I successfully generated mice with altered PPARg levels within the range 40~180%, which normal humans may exhibit because of the polymorphic variations in their genome. This range of difference in mice, however, did not have significant effects on body/fat weights, insulin sensitivity, and blood pressure. Thus, the physiological range of variations in PPARg expression in humans is not likely to have a significant impact on the development of metabolic abnormalities.  Together, my research has explored the impact of variations in PPARg level/activity on the metabolic syndrome. These studies underscore the importance of PPARg in body fat distribution, which may be a critical link between PPARg and the metabolic syndrome.