CHARACTERIZATION OF INSULIN-RESISTANCE AND NIDDM IN TRANSGENIC MICE WITH REDUCED BROWN FAT

We recently created a new model of murine obesity through transgenic a blation of brown adipose tissue (BAT) using a tissue-specific toxigene (6), The goal of the present study was to further define the altered glucose homeostasis and insulin resistance in these transgenic animals , Despite an similar to 30% increase in total body lipid, no abnormali ties were observed in 6-week-old transgenic animals, At the age of 22- 26 weeks, marked obesity in transgenic mice was associated with signif icant increases in blood glucose and plasma insulin levels and an abno rmal response to both intraperitoneal glucose and insulin tolerance te sts, Glucose transport in soleus muscle was reduced, with the response to insulin stimulation blunted by up to 85% in males and 55% in femal es. The total number of insulin receptors was decreased by 36% in musc le and 59% in adipose tissue of transgenic animals, Insulin receptor t yrosine kinase activity, which was assessed following maximal insulin stimulation in vivo, was reduced in transgenic animals by 59% in muscl e and 56% in fat, GLUT4 mRNA and protein was unchanged in muscle of tr ansgenic animals compared with in that of controls but was significant ly reduced in adipose tissue, In conclusion, primary BAT deficiency re sults in the development of glucose intolerance or diabetes and severe insulin resistance with both receptor and postreceptor components. Th ese animals should be a useful model for studies of obesity-linked dia betes and insulin resistance and related complications,