Obesity is characterized by low-grade inflammation, and a growing number of immunologists are devoted to the study of obesity, thus seeding the field of immunometabolism. I entered this field after training in the laboratory that identified the hormone leptin, a key regulator of fat mass. The ground-breaking paper describing the discovery of leptin is a must-read for those new to the field of immunometabolism (Zhang et al., 1994); deservedly, this paper was celebrated in the 2020 Breakthrough Prizes in Life Science.

The ob/ob mouse line, spontaneously generated in the 1950s by the Jackson Laboratories, showed a Mendelian pattern of inheritance of obesity, which suggested a monogenetic mutation controlling fat mass. Consistent with this idea were Coleman’s parabiosis experiments, which indicated that an unknown blood-borne circulating factor normalized the obese phenotype of ob/ob mice (Coleman, 1978). Using positional cloning technology, Jeffrey Friedman and colleagues mapped the ob gene encoding the circulating factor (later named leptin) to chromosome 6 and isolated it by exon trapping, thus identifying the first piece in the puzzle of what regulates whole body fat mass. They also identified adipose tissue as the source of this circulating factor, which informs the brain on the levels of body fat stores via a negative-feedback loop to regulate adipose mass (Halaas et al., 1995).

Leptin resistance is the main culprit of common obesity

The discovery of leptin represented a paradigm shift at a time when mechanistic models of obesity were restricted to voluntary control of food intake and exercise. The identification of leptin also uncovered a novel endocrine system and a better understanding of the pathology of obesity from a biological perspective, similarly to what was accepted for conditions such as cancer, depression and autoimmune diseases.

Leptin resistance is the main culprit of common obesity, yet it is rarely considered in immunometabolism models. I am optimistic that an immunometabolic understanding of leptin resistance could be achieved with a greater appreciation by immunologists of the contribution of leptin.