Insulin depletion leads to adipose-specific cell death in obese but not lean mice

Abstract

Mutation of the obese gene produces obesity, hyperinsulinemia, and compensatory ''overexpression'' of the defective gene. As insulin activates obese gene expression, it seemed possible that hyperinsulinemia might be responsible for overexpression of the gene. To address this question we rapidly neutralized circulating insulin by injection of an insulin antibody. Unexpectedly, insulin depletion in obese (ob͞ob or db͞db) mice caused massive adipose RNA degradation confirmed by histological analysis to result from adipocyte cell death by a largely necrotic mechanism. This effect was not observed in lean littermates and was completely corrected by coadministration of insulin. Comparison of multiple tissues demonstrated that the effect was restricted to adipose tissue. Insulin depletion in obese mice by administration of streptozotocin also led to cell death, but this death was less extensive and appeared to be apoptotic in mechanism. Thus insulin may promote the survival side of the physiological balance between adipocyte survival and death.Obesity is a major health problem in western societies. The excessive accumulation of body fat constitutes a risk factor for noninsulin dependent diabetes mellitus, cardiovascular and cerebrovascular disease, and a number of other pathological conditions (1). Recently, signaling systems have been discovered that serve to regulate body weight and fat accumulation. Leptin, the product of the obese gene, suppresses food consumption and increases energy expenditure (2).Loss of leptin signaling, due to mutation of the obese gene (as in the ob͞ob mouse) or of the leptin receptor (as in the db͞db mouse) leads to massive obesity, hyperglycemia and hyperinsulinemia as in type II diabetes, as well as a 10-to 20-fold over-expression of the leptin message, albeit a defective message (2). Previous findings showed that insulin promotes expression of the obese gene both ex vivo and in vivo (2) (3). To investigate the possibility that the hyperinsulinemia that accompanies obesity in ob͞ob mice might be responsible for the ''overexpression'' of the obese gene in these mice, we injected anti-insulin antibody to rapidly lower the blood insulin level. Unexpectedly, acute neutralization of blood insulin in vivo with a specific anti-insulin antibody resulted in massive adipocyte cell death by necrotic and apoptotic mechanisms. Surprisingly, adipocyte cell death did not occur in normal lean littermates. Moreover, cell death was adipose tissue-specific and did not occur in muscle, liver, spleen, or brain. This result suggests that the hyperinsulinemia associated with obesity may serve to balance the anti-adipogenic signal and promote adipocyte survival. EXPERIMENTAL PROCEDURESMice. Seven-week-old C57BL͞6, C57BL͞6J ob͞ob, and C57BLS͞J db͞db mice were obtained from The Jackson Laboratory and housed under pathogen-free conditions for 1-3 weeks before use. All procedures were performed in accordance with Johns Hopkins University School of Medicine institutional guidelines for animal welfare.Decomple...

p53 Activation in Adipocytes of Obese Mice

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Increased Infiltration of Macrophages in Omental Adipose Tissue Is Associated With Marked Hepatic Lesions in Morbid Human Obesity

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Vitamin A supplementation induces adipose tissue loss through apoptosis in lean but not in obese rats of the WNIN/Ob strain

“…Apoptosis has been described both in WAT and brown adipose tissue (BAT) (Prins et al 1994). Several studies have demonstrated in vitro and in vivo adipocyte apoptosis under various conditions such as growth factor deprivation, dietary conjugated linoleic acid supplementation and streptozotocin administration , Loftus et al 1998, Miner et al 2001, Hargrave et al 2002. Even in patients with malignancy-associated weight loss, apoptosis is detected in abdominal, subcutaneous and omental fat (Prins et al 1994).…”