Insulin Sensitivity and the Onset of Hyperphagia in Fatty Rats

Hyperphagia emerges suddenly after 22 days of age in Zucker fatty (fa/fa) rats, and fatties become visibly obese within days. This rapid increase in growth rate is likely to be associated with substantial changes in glucose metabolism. The objective of these experiments was to determine the relationship between insulin resistance and the onset of hyperphagia. Insulin tolerance tests showed that fatties were remarkably insulin resistant prior to the onset of hyperphagia, hyperinsulinemia, and obesity, but become as insulin sensitive as their lean littermates after the onset of hyperphagia. Furthermore, fatties became increasingly insulin resistant prior to the onset of hyperphagia, and then became as insulin resistant as their lean littermates after the onset of hyperphagia. To determine whether these changes in insulin resistance are associated with changes in expression of the nuclear transcription receptor peroxisome proliferator-activated receptor gamma (PPARg), which improves insulin resistance by increasing lipogenesis in adipose tissue, we measured PPARg and fatty acid synthase (FAS) mRNA and protein at several points in development. PPARg and FAS mRNA expression was induced in fatties after the onset of hyperphagia. PPARg and FAS protein expression increased gradually after the onset of hyperphagia, similar to the changes in insulin sensitivity. These observations suggest that changes in PPARg signaling may play a critical role in promoting the increase in insulin sensitivity after the onset of hyperphagia and perhaps in the promotion of hyperphagia itself.