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The Story of Leptin: A Fat Mouse, a Surgical Experiment and a Missing Hormone
In 1949, workers at the Jackson Laboratory in Maine noticed something odd in a mouse colony: a few animals were enormously fat. The mutation they carried, later named ob (for obese), would eventually reveal a hormone that tells the brain how much fat the body holds.
Key takeaways
- The ob/ob mouse (1949) and the db/db mouse (1966) were both severely obese.
- Douglas Coleman’s parabiosis experiments in the 1970s showed that one strain lacked a blood-borne factor and the other could not respond to it.
- The ob gene was cloned in 1994 by Jeffrey Friedman’s group, and its product was named leptin.
- Most people with obesity have high leptin, not low, which complicated early hopes.
Two fat mouse strains
The ob/ob mouse ate voraciously and grew massive. In 1966, a second obese strain, db/db (diabetes), appeared at the same laboratory. They looked similar, but they behaved differently in the experiment that made them famous.
Parabiosis: sharing a circulation
Douglas Coleman, a researcher at the Jackson Laboratory, used a surgical technique called parabiosis, in which the skin of two animals is joined so that their circulations connect. When an ob/ob mouse was joined to a normal mouse, the obese mouse ate less and lost weight. When a db/db mouse was joined to a normal mouse, the normal one stopped eating and lost weight, but the db/db mouse stayed obese. Coleman reasoned that ob/ob mice lacked a circulating satiety factor, while db/db mice made the factor but could not respond to it. It was a remarkable inference, made years before the molecules were known.
Cloning the gene
Finding the actual molecule took years of positional cloning in the early 1990s. In 1994, Friedman and colleagues at Rockefeller University reported the cloned ob gene and its protein, made in fat cells. They called it leptin, from the Greek leptos, meaning thin. Injecting leptin into ob/ob mice reduced their food intake and weight. The db gene was soon shown to encode the leptin receptor, completing Coleman’s picture.
What leptin does
Leptin is released by adipose tissue in proportion to fat stores. It acts on neurons in the hypothalamus, where it inhibits appetite-promoting NPY/AgRP neurons and activates POMC neurons, tying into the melanocortin system (see the agouti mouse story). The full map is in the appetite hormone map.
The complication
The excitement was tempered by what came next. In people, rare mutations that remove leptin cause severe obesity, and replacing it corrects the problem. But in common obesity, leptin levels are high, and giving more does not help much. The concept of leptin resistance, a reduced response to high levels, has been proposed, although its mechanism is still debated. Leptin also falls sharply during weight loss, which is part of why the body defends its stores (see why weight loss plateaus).
Lessons from the story
- Elegant physiology experiments can predict a molecule years before it is found.
- A mouse result can be perfect for the mouse and only partly true for people (see the evidence ladder).
- Mutations are a way to find the pathways that matter.
The bottom line
Leptin did not become the cure for obesity, but it opened the whole modern field of appetite hormones, and it began with a few overweight mice in Maine.
Related reading
- The Appetite Hormone Map: Ghrelin, Leptin, PYY, GLP-1, CCK, Amylin and the Brain
- The Story of the Yellow Obese Mouse: How Coat Color Led to the Brain’s Appetite Switch
- The Evidence Ladder: How to Read Peptide Research Without Being Fooled
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.