An investigator is studying weight regulation using experimental mouse models. Knockout mice are created with a homozygous mutation in the gene coding for the leptin receptor. This mutation prevents the receptor from binding leptin and initiating its normal signaling cascade. The knockout mice are allowed to feed at will, and their body mass index (BMI) and serum leptin levels are measured and compared with control mice. On the graph below, area C represents the normal relationship between BMI and leptin in a control mouse.
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Which of the following areas represents the expected relationship between BMI and serum leptin levels in a leptin receptor mutant mouse?
Leptin is a protein hormone that plays an important role in regulating appetite and metabolism. It is produced primarily in adipocytes, and large fat cells produce more leptin than small ones. Serum leptin concentrations are highly correlated with body fat content.
Leptin decreases food intake in the following important ways:
The knockout mouse described is homozygous for a mutation in the gene encoding the leptin receptor (db/db), resulting in ineffective leptin signaling. As a result, these mice become hyperphagic and profoundly obese. As leptin production is normal in these mice, leptin levels are elevated due to the increased lipocyte mass. In contrast, mice that are homozygous for a mutation resulting in impaired leptin production (ob/ob) also become hyperphagic and profoundly obese, but their leptin levels are low (Choice A).
Human obesity resulting from mutations in the leptin receptor and the leptin gene has been described. However, most obese individuals do not have either of these mutations. Instead, it is thought that the sustained elevation in leptin levels from the enlarged fat stores results in leptin desensitization. Thus, obese individuals become resistant to the effects of leptin in a manner similar to the development of insulin resistance in type 2 diabetes.
(Choice D) Low leptin and low BMI correlate with low adipocyte stores and may be seen after prolonged starvation.
(Choice E) With intact receptor signaling, elevated leptin levels (ie, from exogenous leptin administration) would result in weight loss.
Educational objective:
Leptin is a protein hormone produced by adipocytes in proportion to the quantity of fat stored. Leptin acts on the arcuate nucleus of the hypothalamus to inhibit production of neuropeptide Y (decreasing appetite) and stimulate production of alpha-MSH (increasing satiety). Mutations in the leptin gene or receptor result in hyperphagia and profound obesity.