Development of insulin resistance and hyperphagia in Zucker fatty rats

Abstract

The onset of hyperphagia in the Zucker fatty (fa/fa) rat occurs on a single day in postnatal development and could be driven by an increase in insulin sensitivity. To test this hypothesis, we performed insulin tolerance tests at several points in development. In rapidly growing juvenile rats, fatty rats are as insulin sensitive as lean rats at 4 wk of age but become increasingly insulin resistant as they became obese. During the suckling to weaning transition, fatty rats are insulin resistant at 2 wk of age, when they are exclusively suckling; they are also insulin resistant at 3 wk of age, when they are suckling and consuming solid food, but not hyperphagic. By 4 wk of age, when fatty rats are hyperphagic, they are as insulin sensitive as their lean littermates. These data indicate that fatty rats experience two phases of insulin resistance, punctuated by a brief period of insulin sensitivity that follows the onset of hyperphagia. To determine whether the increase in insulin sensitivity could be driving the onset of hyperphagia, insulin tolerance tests were performed from 21 to 27 days of age. Obese and lean rats became increasingly insulin resistant from 21 to 23 days of age and then became as insulin sensitive as lean rats by 25 days of age. These data show that increased insulin resistance precedes the onset of hyperphagia and increased insulin sensitivity follows the onset of hyperphagia. This pattern suggests that developmental perturbations in insulin signaling are likely to be involved in the onset of hyperphagia.

FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats

“…Obese Zucker fa/fa rats develop a hyperphagia-driven obesity as a consequence of spontaneous mutation in the leptin receptor ( 15,16 ). Impaired leptin signaling leads to hyperinsulinemia, hyper-glycemia, hyper-triglyceridemia, hyper-cholesterolemia, insulin resistance, and liver fat accumulation and increased aminotrasnferases plasma levels.…”

“…Zucker (fa/fa) rats, harboring a loss-of-function mutation of the leptin receptor, exhibit hyperphagia and hyperleptinaemia and develop obesity and insulin resistance ( 15 ). Because obesity, type 2 diabetes, and liver steatosis are distinctive features of NAFLD, Zucker (fa/fa) rats can be considered a model for NAFLD ( 1,15,16 ).…”

“…Because obesity, type 2 diabetes, and liver steatosis are distinctive features of NAFLD, Zucker (fa/fa) rats can be considered a model for NAFLD ( 1,15,16 ). Agents that target insulin sensitivity have been used for treatment of metabolic disorder.…”

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

“…In addition, mutants also show secondary complications underlying obesity such as renal and cardiovascular diseases observed in other obese models. [21][22][23][24] Interestingly, histopathological studies reveal altered islet cytoarchitectecture in the Figure 5. Bright field images, functional assay and ultrastructural analysis of primary islet cultures.…”

Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

“…Glucagon and insulin were given intraperitoneally 10 min before or 10, 30 or 60 min after the induction of MCAO. Insulin doses of 2 U/kg to wild-type (WT) and 3 U/kg given to diabetic rats were based on the literature (20,40), as well as on a preliminary test that we performed to decrease plasma glutamate with insulin to the same levels achieved with glucagon. The higher dose of insulin in diabetic rats was due to the insulin resistance typical of type II diabetes.…”