Leptin, a hormone central to energy balance, was first conceptualized in 1958 through Hervey’s parabiosis experiments, which proposed a circulating satiety factor targeting the ventromedial hypothalamus (VMH). His work, followed by Kennedy’s hypothesis of a weight-regulating feedback loop, laid the groundwork for identifying leptin. This hormone was later isolated in 1994 by Jeffrey L. Halaas, revealing its role in appetite suppression and weight regulation. Leptin’s encoding gene, ob, primarily expressed in adipose tissue, provides leptin’s signal through a network of receptors distributed across brain regions and peripheral tissues, especially concentrated in the hypothalamus. Upon binding, leptin receptors activate intracellular pathways like JAK-STAT, PI3K, MAPK, and AMPK, which collectively mediate appetite control, metabolic rates, and energy storage adjustments, particularly during fasting or caloric deficits. Clinically, leptin resistance is frequently observed in obesity and type 2 diabetes (T2DM), where leptin’s ability to modulate glucose homeostasis is impaired, exacerbating insulin resistance and cardiovascular complications. Additionally, studies suggests that leptin has been involved in memory formation and immune response, playing an important role in neurobiology function.
You may find weight loss to be one of the most challenging tasks in life. After each brief period of dieting, a 'surge in appetite' often follows. This phenomenon is widely observed in nature. Scientists identified early on that decreases in adiposity, induced by fasting or surgical removal, tend to result in increased appetite and reduced energy expenditure, eventually restoring body weight to its previous level.
To uncover the mechanisms behind this, Kennedy hypothesized the existence of a homeostatic system capable of monitoring changes in energy stores and inducing compensatory changes in food intake and energy expenditure, thus maintaining fat stores at a set point. The first experimental evidence for such a regulatory mechanism came from Hetherington, who found that lesions in the ventromedial hypothalamus (VMH) of rats led to hyperphagia and fat deposition, although he did not offer a convincing explanation for this phenomenon.
In 1958, Hervey utilized parabiosis techniques by pairing two rats and lesioning the VMH in one of them. He observed that the rat with the lesion exhibited overactivity and voracity, with rapid weight gain, while the other rat displayed a marked decrease in appetite, refusing food, becoming increasingly listless and inactive, and eventually dying of starvation. Hervey proposed the existence of a circulating satiety factor targeting the VMH, which inhibited appetite, increased fat oxidation, and lowered body weight. In this experiment, elevated levels of the circulating satiety factor from the obese rat inhibited the intact rat's food intake; the obese rat, however, could not respond to the elevated levels of this putative satiety factor due to VMH lesions.
Researchers then pursued the isolation and characterization of this endogenous circulating satiety factor. In 1950, Ingalls reported a new mutation called obese, symbolized as 'ob,' in which homozygous mutants exhibited rapid weight gain, reaching weights approximately four times that of normal animals. Naturally, scientists speculated that the product of the ob gene might be closely associated with the hypothesized satiety factor, potentially even being the sought-after factor. However, classical genetics did not provide sufficient insights to elucidate the factor’s chemical nature, and new evidence was eagerly awaited.
This evidence came 20 years later. It was not until 1994 that the ob gene was precisely mapped and identified through cloning technology. Soon after, Jeffrey L. Halaas conducted detailed analyses of the ob gene product and its physiological functions. He discovered that this 16 kD protein significantly reduced food intake and body weight in mice, with an endocrine role in regulating fat storage. Consequently, he named the protein leptin, derived from the Greek root leptos, meaning thin.