Restoration of in β cells of null mice does not prevent hyperinsulinemia and hyperglycemia.

OBJECTIVE

The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre- to disrupt the leptin receptor gene () in β cells, but variable results were obtained. Furthermore, recombination of was observed in the hypothalamus or exocrine pancreas, in addition to the β cells, and in non-β cells may have compensated for the loss of in β cells, thus making it difficult to assess the direct effects of in β cells. To determine the significance of exclusively in β cells, we chose to selectively restore in β cells of null mice ().

MATERIALS AND METHODS

We used a mouse model in which endogenous expression of was disrupted by a -flanked transcription blocker (), but was restored by recombinase knocked into the gene, which is specifically expressed in β cells (Cre). We bred and Cre mice to generate and Cre mice, as well as and Cre littermate mice. Male and female mice were weighed weekly between 6 and 11 weeks of age and fasting blood glucose was measured during this time. Oral glucose was administered to mice aged 7-12 weeks to assess glucose tolerance and insulin secretion. Relative β and α cell area and islet size were also assessed by immunostaining and analysis of pancreas sections of 12-14 week old mice.

RESULTS

Male and female mice, lacking whole-body expression of , had a phenotype similar to mice characterized by obesity, hyperinsulinemia, glucose intolerance, and impaired glucose stimulated insulin secretion. Despite restoring in β cells of mice, fasting insulin levels, blood glucose levels and body weight were comparable between Cre mice and littermates. Furthermore, glucose tolerance and insulin secretion in male and female Cre mice were similar to that observed in mice. Analysis of pancreatic insulin positive area revealed that restoration of in β cells of mice did not prevent hyperplasia of insulin positive cells nor did it rescue Glut-2 expression.

CONCLUSION

Collectively, these data suggest that direct action of leptin on β cells is insufficient to restore normal insulin secretion and glucose tolerance in mice without leptin receptor signaling elsewhere.