INSULIN DEPLETION LEADS TO ADIPOSE-SPECIFIC CELL-DEATH IN OBESE BUT NOT LEAN MICE

Mutation of the obese gene produces obesity, hyperinsulinemia, and com pensatory ''overexpression'' of the defective gene. As insulin activat es obese gene expression, it seemed possible that hyperinsulinemia mig ht be responsible for overexpression of the gene. To address this ques tion we rapidly neutralized circulating insulin by injection of an ins ulin antibody. Unexpectedly, insulin depletion in obese (ob/ob or db/d b) mice caused massive adipose RNA degradation confirmed by histologic al analysis to result from adipocyte cell death by a largely necrotic mechanism. This effect was not observed in lean littermates and was co mpletely corrected by coadministration of insulin. Comparison of multi ple tissues demonstrated that the effect was restricted to adipose tis sue. Insulin depletion in obese mice by administration of streptozotoc in also led to cell death, but this death was less extensive and appea red to be apoptotic in mechanism. Thus insulin may promote the surviva l side of the physiological balance between adipocyte survival and dea th.