Metabolism: The discovery of leptin

Leptin is a 167-amino acid polypeptide hormone that controls appetite and feeding behavior. Because the amount of leptin in the blood is directly proportional to the amount of adipose tissue (body fat), obesity causes high levels of leptin (hyperleptinemia). This can cause a lack of sensitivity to leptin, a condition known as acquired leptin resistance, which further contributes to sustained obesity. Leptin deficiency or leptin insensitivity is caused by genetic mutations, which, in rare cases, lead to severe and recalcitrant obesity.

Leptin’s discovery followed pioneering work by D.L. Coleman and colleagues using parabiotic pairs of mice. Parabiosis refers to a skin-to-skin anastomosis formed by surgically joining two mice from the shoulder to the pelvic girdle. Within 3-4 days, after the wound has healed, the parabiotic pair shares a common blood supply.

Coleman initially connected the circulatory system of a lean wild-type (wt) mouse with the circulatory system of an obese db/db mouse. The lean mouse eventually died of starvation, while the db/db mouse lived on, unaffected. In order to explain this result, Coleman hypothesized that the db/db mice produce a circulating molecule that, when introduced to the lean mouse via parabiosis, causes the lean mouse to cease eating, eventually leading to death by starvation. The results of this experiment are shown in Figure 1.

Figure 1 Results of parabiosis experiment with db/db and lean mouse

Coleman also made parabiotic pairings with ob/ob obese mice, which have a different obesity-causing mutation. In a pairing of an ob/ob mouse with a lean wild-type mouse, he observed reduced weight gain and food intake in the ob/ob mouse, and the paired mice lived for months (until the end of the experiment). Parabiosis of an ob/ob mouse with a db/db mouse allowed Coleman to make his profound conclusions. In this pairing, the ob/ob mouse eventually starved to death after 20–30 days while the db/db mouse gorged on food and gained weight at normal rates. The results of the experiments with ob/ob mice are shown in Figure 2.

Figure 2 Results of parabiosis experiments with ob/ob and lean mouse (top) and ob/ob and db/db mouse (bottom)