The discovery of leptin
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The discovery of leptin
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[post_date] => 2024-12-23 18:23:02
[post_date_gmt] => 2024-12-23 23:23:02
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
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)
Article and figures adapted from Reichenbach et al, Hypothalamic Control of Appetite and Energy Metabolism, 2012.
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[question] => How many nucleotides long is the gene that codes for the hormone leptin?
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[answer] => 4
[description] => Reason for Correct Answer:
Leptin is a 167 amino acid protein.
According to the central dogma of molecular biology, each amino acid in a polypeptide is coded for by a three nucleotide sequence in the gene that codes for the polypeptide.
Eukaryotic genes contain a start codon, which codes for an amino acid (methionine), and a stop codon, which does not.
Eukaryotic genes contain introns, sequences of nucleotides within genes that do not correspond to amino acids in the functional protein.
The leptin gene is therefore greater than 167 x 3 + 6 base pairs nucleotides long.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Exactly 167 x 3 base pairs
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[each_answer] => B. Exactly 167 x 3 + 3 base pairs
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[each_answer] => C. Exactly 167 x 3 + 6 base pairs
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[each_answer] => D. Greater than 167 x 3 + 6 base pairs
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[quiz_unique_key] => 1403770772
[question] => An experiment is designed in which synthetic leptin is administered intravenously to db/db mice and ob/ob mice: which strain would most likely experience a cessation of the symptoms associated with their respective genetic mutations?
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[answer] => 2
[description] => Reason for Correct Answer:
The experiments show that, when parabiosed with lean mice with normal levels of circulating leptin, ob/ob mice experience a cessation of symptoms associated with their mutation.
However, when parabiosed with lean mice with normal levels of circulating leptin, no change occurs in db/db mice.
This suggests that leptin would be a helpful treatment for ob/ob mice but not for db/db mice.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Db/db mice only
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[each_answer] => B. Ob/ob mice only
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[each_answer] => C. Both strains
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[each_answer] => D. Neither strain
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[quiz_unique_key] => 1403770772
[question] => Which of the following is the best explanation for the results observed during the parabiosis experiments involving db/db mice?
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[answer] => 2
[description] => Reason for Correct Answer:
Leptin normally causes decreased appetite and decreased weight as long as (a) it is actually present and (b) cells can properly respond to it. The obese db/db mice have an issue with one of these things, resulting in their obesity.
Figure 1 shows that the db/db mice transmitted a circulating factor that caused starvation in the normal mice. But, the normal mice did not transmit anything helpful to the db/db mice.
This suggests that db/db mice have a large amount of leptin in their circulation – so much that it causes the normal mice to starve.
The db/db mice must therefore be obese because their cells are insensitive to leptin, likely due to a mutated and inactivated transmembrane receptor. Lack of response to leptin in their cells leads to a loss of negative feedback on leptin secretion, resulting in hypersecretion of leptin in these mice.
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[each_answer] => A. The db mutation results in a transmembrane receptor being constitutively active in db/db mice, resulting in increased sensitivity in leptin-sensitive cells and decreased secretion of leptin by leptin-producing cells.
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[each_answer] => B. The db mutation inactivates a transmembrane receptor on leptin-sensitive cells, resulting in leptin resistance in leptin-sensitive cells and hypersecretion of leptin by leptin-producing cells.
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[each_answer] => C. The db gene mutation results in a transcription factor being constitutively active in db/db mice, resulting in hypersecretion of leptin by leptin-producing cells in db/db mice.
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[each_answer] => D. The db gene inactivates a transcription in db/db mice, resulting in hyposecretion of leptin by leptin-producing cells.
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[question] => Which of the following could account for the effects of the ob gene mutation as observed in Coleman’s experiments?
I. The mutation occurs in the leptin gene.
II. The mutation occurs in the gene that codes for a chaperone protein involved in post-translational modification of leptin.
III. The mutation occurs in the gene that codes for a transcription factor that acts as a co-repressor of the leptin gene.
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[answer] => 2
[description] => Reason for Correct Answer:
The results of the experiments show that ob/ob mice normalize in weight when connected to normal mice.
This suggests that there is a circulatory factor that is transmitted from normal mice to ob/ob mice that allows their weight to normalize. In the context of this passage, we know that the circulatory factor is leptin, which controls hunger and appetite.
This means that ob/ob mice normally don’t produce normal leptin and this is the cause of their obesity. So, we are looking for genetic mutations that would result in a lack of functional leptin in the body.
A mutation in the leptin gene could result in a lack of leptin production. (I is correct.)
A mutation in a chaperone protein could result in leptin misfolding and a lack of useful leptin in circulation. (II is correct.)
A mutation in a transcription factor that acts as a co-repressor for the leptin gene would not likely decrease leptin production; it would likely increase leptin production by decreasing the amount of its repressor present. (III is not correct.)
)
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[0] => Array
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[each_answer] => A. III only
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[each_answer] => B. I and II only
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[each_answer] => C. I and III only
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[each_answer] => D. I, II, and III
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[question] => In addition to leptin, average levels of which hormone tend to increase with weight gain?
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[answer] => 3
[description] => Reason for Correct Answer:
Cortisol is a glucocorticoid hormone. One of its biological effects is to increase plasma glucose.
Leptin is a hormone that helps control appetite and eating. Paragraph 1 states that the amount of leptin in the blood is directly proportional to the amount of adipose tissue (body fat). This means that overweight people generally have higher leptin levels. Look at the passage figures to see if there is another hormone affected by weight gain and loss in a similar way.
The passage figures show that insulin goes down when the rats lose weight.
This is because insulin levels tend to rise with weight gain and obesity, similar to leptin. Insulin is a hormone produced by the pancreas that plays a central role in regulating blood sugar levels and facilitating the uptake of glucose into cells for energy. As an individual gains weight and becomes obese, their body’s insulin resistance often increases. This means that the body’s cells become less responsive to the effects of insulin, leading to higher levels of insulin in the blood. This phenomenon is closely linked to the development of type 2 diabetes and is a hallmark of metabolic syndrome associated with obesity.
Reason for Incorrect Answer:
A. Increased thyroid hormone results in decreased weight, which would result in decreased leptin levels.
B. Glucagon, produced in response to fasting and increased energy requirements, would not rise with increased body fat, like leptin.
D. Ghrelin is the “hunger hormone,” which acts antagonistically to leptin; they should not rise simultaneously.
)
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[each_answer] => A. Thyroid hormone
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[each_answer] => C. Insulin
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[quiz_unique_key] => 426016249
[question] => Leptin acts on what part of the brain to control hunger?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
Ghrelin and leptin act on the same part of the brain to control hunger.
This is also the part of the brain that helps regulate circadian rhythms, body temperature, autonomic functions, emotion, and behavior.
This is also the part of the brain that produces hormones that act on the pituitary gland.
This part of the brain is the hypothalamus, shown in blue below. The hypothalamus sits above the pituitary gland, to which it sends hormones through a specialized system of blood vessels called the hypothalamic–pituitary portal system; it also sends nerve fibers to the autonomic ganglia and other parts of the body.
https://commons.wikimedia.org/wiki/File:1806_The_Hypothalamus-Pituitary_Complex.jpg
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[each_answer] => A. Hypothalamus
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[each_answer] => B. Medulla oblongata
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[each_answer] => C. Pons
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[each_answer] => D. Cerebellum
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Figure 1
Figure 2
