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Insulin depletion leads to adipose-specific cell death in obese but not lean mice
T M Loftus1, F P Kuhajda, M D Lane
1Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
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 (ob/ob or db/db) 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.
Insights
Insulin depletion in obese mice causes fat cell death, unlike in lean mice. Insulin administration reverses this effect, suggesting insulin promotes fat cell survival.
Area of Science:
- Metabolic research
- Obesity research
- Adipose tissue biology
Background:
- Obesity gene (ob) mutations cause obesity and hyperinsulinemia.
- Insulin normally activates obese gene expression.
- Hyperinsulinemia's role in obese gene overexpression was unclear.
Purpose of the Study:
- To investigate if hyperinsulinemia causes obese gene overexpression.
- To determine the effect of insulin depletion on adipose tissue in obese mice.
Main Methods:
- Neutralizing circulating insulin using insulin antibodies in obese (ob/ob, db/db) and lean mice.
- Histological analysis to assess adipocyte cell death and RNA degradation.
- Administering streptozotocin to induce insulin depletion in obese mice.
Main Results:
- Insulin depletion in obese mice led to massive adipose RNA degradation and adipocyte cell death (necrotic mechanism).
- This effect was absent in lean mice and reversed by insulin coadministration.
- Insulin depletion via streptozotocin also caused adipocyte death, but it was less extensive and apoptotic.
Conclusions:
- Insulin is crucial for maintaining adipocyte survival in obese mice.
- Insulin depletion disrupts the balance between adipocyte survival and death.
- Findings suggest a novel role for insulin in preventing fat cell death.