The Leptin Story

Leptin is a peptide hormone that was discovered in 1994 by a Scientist called Friedman. Fat cells produce leptin and this signal is used in a feedback loop to allow the maintenance of correct body weight. Mice missing the leptin gene (ob/ob mice) grow incredibly fat because their hypothalamus does not receive a leptin signal from the adipose tissue. As a result appetite and energy utilisation are not modified in response to growing adipocyte stores and the mice become incredibly fat. However, when these mice are injected with leptin, they return to near normal body weight in a very short time because the leptin signal causes an increase in energy expenditure and increased activity. When this was discovered it was hailed as a breakthrough in obesity treatment. It was assumed that obese human like ob/ob mice had a deficiency of leptin, and injecting them with the peptide hormone would return them to normal weight. However, there was a twist to this story that researchers did not anticipate, which left them disappointed.

When obese humans were injected with leptin, there was no weight loss effects. The reason for this is that obese people do not have low levels of leptin like the ob/ob mice. In fact obese humans have levels of leptin that are higher than normal. It is not the signal from the adipocytes that is faulty, but instead the interpretation of that signal by the hypothalamus. In obesity the hypothalamus becomes insensitive to the leptin signal, and so despite high levels of leptin, their appetite and energy regulatory systems are not modified in response to gaining weight. The leptin resistance is thought to be a secondary consequence of insulin resistance, which in turn is believed to be caused by eating a low quality diet high in sugar. The fructose component of the sugar increases flux through the de novo lipogenesis pathway, and this creates fatty acids that accumulate in tissues and interfere with the insulin signal cascade. There is no miracle injection that can reverse this process as for the mice, only eating a high quality diet is effective.

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