The Gene Encoding Leptin
The Gene Encoding Leptin
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The Discovery of The Gene Encoding Leptin
Our current textbooks teach us that the hypothalamus is an important integration site for adiposity and satiety signals, along with nutrients and information related to the rewarding properties of food (pleasant taste, good memories, good company). This of course was not always textbook information. Some of the earlier clues for this came from experiments by G.R. Hervey in the late 1950s. He was the first to use parabiosis to predict that a circulating factor existed that relays information on our body’s fat mass to the hypothalamus.
Parabiosis is an experimental paradigm where two animals are surgically joined in a way that they will develop a shared circulation. Factors circulating in either of the ‘parabionts’ could thus cross over into the circulatory system of the other.
Side note, such experiments, like any animal studies, are subject to tight ethical oversight where the scientific value is balanced against the degree of pain or discomfort animals experience. Obtaining approval for such parabiosis experiments today would require strong justification and could well be denied.
Hervey’s experiment started with a rat where he damaged (lesioned) the VentroMedial Hypothalamus (VMH). He then waited for some time before parabiosing this animal to a normal lean rat.
Hervey hypothesized that there existed a circulating factor (i.e. a hormone) that acted as a ‘lipostat’ by conveying information about fat mass to the VMH and that damaging the VMH would make the animal unable to respond to this factor. The VMH-lesioned animal would start to eat excessively (hyperphagia) and become morbidly obese as a consequence (think back of the girl with the craniopharyngoma). The lean parabiont however, would stop eating and die of starvation. Question: Why this is the case. Please make sure you understand this before moving on.
Experiments that suggested that the lipostat predicted from Hervey’s experiments was a single gene were done by Douglas Coleman. He maintained large colonies of mice and observed by chance (and by paying attention) that some mice in one of his colonies developed a pronounced morbid obesity phenotype, accompanied by hyperglycemia. These obese mice are infertile, but by mating the parents of offspring that developed this obese phenotype he noticed that about 1 in 4 pups developed obesity. Based on this he concluded that he was dealing with a single recessive allele that he named the obese allele (abbreviated as ob).
Around the same time but in a different colony of mice, he discovered animals that also were morbidly obese and diabetic (and could not produce offspring either). These mice too occurred in a frequency of 1 in 4 pups. He concluded that this too was a single recessive allele and he named this allele ‘diabetes’ abbreviated as db.
Based on this information, he then hypothesized that one of these alleles encoded a soluble factor while the other might encode its receptor. In order to test this hypothesis and determine which allele encoded the signal and which the receptor, Coleman carried out the following series of parabiosis experiments, with the following outcomes.
Assignment: Based on this information, explain in your own words (250 of them or more) how Coleman was able to conclude which allele encoded the signal and which the receptor.
To do so: 1. explain for each of the first three parabiosis experiments (a-c) the outcome that is described and why these experiments all pointed in the same direction. Hint: you can discuss these in any order. 2. Explain the purpose of the parabiosis experiment of the two lean mice in (d). 3. Include in your answer how Coleman was able to easily rule out before doing these parabiosis studies that the ob and db alleles with their highly similar phenotypes were two mutations of the same gene.
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