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Group 1
Leptin’s Legacy
Excerpts from: http://www.hhmi.org/bulletin/mar2003/leptin/leptin2.html
Scientists, of course, approach any notion of a magic bullet with supreme skepticism, if
not total disdain. But electrified by leptin's potential for the treatment of obesity — the
mice had lost 30 percent of their body weight in just two weeks — business pounced on
the discovery. With more than half of U.S. adults overweight or obese, a cure would be a
major advance in public health. Moreover, the treatment was sure to be a cash cow for its
marketers. The biotech company Amgen paid $20 million to license the hormone.
When Amgen sponsored a large clinical trial of leptin, however, few participants lost
weight, dashing hopes that the hormone could curb obesity. "Treatment with high-dose
leptin did not achieve the clinical or commercial hurdles necessary," says Amgen
spokesperson Christine Brown. "The company is not looking further at using leptin in
normal adult obesity."
The leptin story began in 1950, when researchers at The Jackson Laboratory in Bar
Harbor, Maine, noticed that they had a strain of mice that were obese, lethargic, insulinresistant and constantly hungry. This so-called ob/ob mouse, Friedman says, "lives in a
state of perceived starvation, so ironically it becomes fat." The scientific explanation
finally emerged in 1994, when Friedman and his colleagues found the mutated ob gene
responsible for the syndrome. The next year, they purified the normal ob gene's product,
a hormone they dubbed leptin for the Greek word leptós, which means "thin." When they
gave the obese mice leptin supplements, the animals lost weight, became more active and
began responding to insulin.
In retrospect, it seems clear why so many people in the Amgen clinical trial failed to lose
weight, says Friedman. Obese people have many fat cells, and they generally make lots
of leptin. Therefore, obesity results more often from a failure to respond to leptin than
from an absence of leptin.
Although most people in the trial may have had sufficient leptin, a subset was probably
deficient in the hormone, says Friedman. "Fifteen to 20 percent of the obese people [in
the study] did in fact lose significant amounts of weight. A key unresolved issue concerns
the plasma level of the hormone below which a robust biologic response can be
predicted," he adds.
"I don't want to protest too much, but it's as if we found that the majority of adult-onset
diabetics don't respond to insulin, and concluded that insulin has nothing to do with
lowering glucose." In other words, leptin resistance in the majority of participants may
have masked leptin deficiency in the minority. Friedman and his colleagues are now
trying to identify obese people who have low concentrations of leptin and might therefore
benefit from supplements. To treat leptin resistance, scientists must have a better
understanding of the signaling pathways activated by the hormone.
"Leptin is designed to measure the amount of fat you carry, and once you have a
molecule that can signal that, it's logical that it would send that signal to a number of
physiologic systems."
The leptin gene apparently conferred a selective advantage on our ancestors by enabling
them to survive lean times. These days, the challenge in developed societies is to remain
lean during flush times: Obesity and diabetes are far more threatening than starvation.
Although leptin was not a magic bullet for obesity, many researchers say the discovery of
the hormone has changed forever the study of obesity, diabetes and metabolism. "Leptin
was so successful in the rodent model that people immediately became excited about it as
an obesity treatment factor," says Gorden. "In reality, that was probably an enormous
leap of faith."
Leptin
Exerpts from
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/bodyweigh
t/leptin.html
Leptin (from the Greek leptos, meaning thin) is a protein hormone with important effects
in regulating body weight, metabolism and reproductive function. The protein is encoded
by the obese (ob) gene. Leptin is expressed predominantly by fat cells. Leptin receptors
are highly expressed in areas of the hypothalamus known to be important in regulating
body weight.
Leptin in an important component in the long term regulation of body weight.
Genetically obese mice with inactivating mutations in the ob gene or the gene
encoding the leptin receptor (db gene) have been known for many years and were
instrumental in the initial cloning of the ob gene. Recent studies with obese and nonobese humans demonstrated a strong positive correlation of serum leptin concentrations
with percentage of body fat, and also that there was a higher concentration of ob mRNA
in fat from obese compared to thin subjects. It appears that as adipocytes increase in size
due to accumulation of triglyceride, they synthesize more and more leptin.
Daily injections of leptin into ob/ob mice (i.e. the obese mutants unable to synthesize
leptin) led to a dramatic reduction in food intake within a few days, and to roughly a 50%
reduction in body weight within a month. Weight loss resulting from administration of
leptin appears to result from a combination of at least two fundamental effects:
 Decreased hunger and food consumption

Increased energy expenditure
As expected, injections of leptin into db/db mice, which lack the leptin receptor, had no
effect. When leptin was given to normal mice, they lost weight, showed profound
depletion of adipose tissue and manifest increases in lean mass.
The mechanisms by which leptin exerts its effects on metabolism are largely
unknown and are likely quite complex.
Control of Leptin Synthesis and Secretion
The amount of leptin expressed by fat cells correlates well with the lipid content of
the cells.
Disease States
Mice with inactivating mutations in the gene encoding leptin or its receptor have
indistinguishable, recessive phenotypes of obesity, with roughly
three times the body weight and five times the fat mass of normal
mice. They also manifest diabetes, and show cold intolerance,
depressed immune function and infertility.
Blood concentrations of leptin are usually increased in obese
humans, suggesting that they are in some way insensitive to
leptin, rather than suffering from leptin deficiency. Mutations in
ob or db genes appear to be a very rare cause of morbid obesity in
humans, but both have been described. The effect of such mutations
on body weight is dramatic, as shown here. The figure to the right
depicts the growth curve for a young girl found to have
homozygous inactivating mutations of the ob gene, contrasted to
normal children (2nd to 98th percentiles).
Will ob protein be useful for treating human obesity? Perhaps,
but considerable work remains to be done to characterize its effects and, as described
above, it appears that frank deficiencies in leptin secretion are a rare cause of human
obesity. Leptin therapy will require either frequent injections or genetic therapy,
precluding its use for trivial purposes.
GROUP 2: Hello Protein, Goodbye Fat
From: http://news.sciencemag.org/sciencenow/2006/09/06-02.html
A high protein diet can prevent weight gain by curbing short-term appetite. But just how
this diet works on a physiological level has remained a mystery. Now, a new study
suggests that the key is a tiny protein fragment called peptide YY3-36 (PYY3-36), which
dampens hunger in response to high levels of dietary protein.
In August 2002, endocrinologist Stephen Bloom and colleagues at Imperial College
London showed that when they injected PYY3-36 into rodents and humans, it decreased
hunger for 12 hours or more. Rodents on the peptide also curbed their weight gain,
leading some to herald PYY3-36 as a potential new anti-obesity drug. However, not all
groups have been able to replicate these results, leaving the peptide's promise in the
lurch.
A former member of Bloom's team, endocrinologist Rachel Batterham of the University
College London and colleagues, took another stab, this time from a different angle. They
first fed a group of normal-weight and obese men a diet high in either protein,
carbohydrate, or fat. As expected, volunteers on the high-protein diet felt significantly
less hungry than those on the other diets for up to 3 hours after the meal. The high-protein
dieters also had the highest levels of PYY3-36 in their blood than the other dieters. Mice
showed similar effects, and high blood levels of PYY3-36 in the rodents corresponded to a
reduction in the mRNA levels of certain fatness-inducing messenger proteins in the brain.
To seal the deal, the team created a knockout mouse that lacked the PYY gene. The
knockouts were obese and loved to eat: by 10 weeks of age, PYY knockout mice weighed
about 37.5% more than normal mice and had about 12% more body fat. A high-protein
diet did not curb their hunger. Giving PYY3-36 to the knockout mice led to a drastic
reduction in their eating habits and consequently their body fat and body weight. The
wild-type mice showed little or no change with the same treatment, the researchers report
in this month's issue of Cell Metabolism.
The new study hasn't entirely settled things. "There are still elements of controversy,"
says endocrinologist Jeffrey Flier at the Beth Israel Deaconess Medical Center in Boston,
Massachusetts. The relationship between PYY levels and dietary protein is "extremely
well supported by the data," he says, but in the light of previous work by two other
groups who failed to get an obese phenotype with slightly different PYY knockout mice,
future work is needed to reconcile this discrepancy.
GROUP 3: 'Hunger Hormone' May be Key in Weight Loss – Study is the First to
Document the Effects of Low-calorie Dieting Verses Gastric Bypass Surgery on
Ghrelin Levels
Release 5 p.m. ET May 22, 2002 from
http://www.research.va.gov/news/press_releases/hungerhormone052202.cfmSEATTLE - Thousands of obese Americans know firsthand
that gastric bypass surgery can achieve long-term weight loss when dieting, exercise and
medications have failed. The reason for the difference may hinge on a recently
discovered appetite-stimulating hormone, according to an article in the May 23 New
England Journal of Medicine.
A study led by a team at the Veterans Affairs (VA) Puget Sound Health Care System and
the University of Washington (UW) compared blood samples from dieters and gastricbypass patients and found dramatic differences in the levels of "ghrelin," a hormone
secreted by the stomach. The hormone was first identified by Japanese researchers in
1999, and was shown by British scientists last year to trigger appetite in humans – the
first known hormone to do this.
The new findings may explain why keeping off excess weight through dieting, exercise
or even medication is often a constant uphill battle, whereas obese patients who lose up to
200 pounds or more through gastric bypass surgery tend to keep off the pounds
permanently. The study shows that dieting raises ghrelin, while gastric bypass surgery
sharply reduces it, almost to undetectable levels. The research is the first to document the
effects of low-calorie dieting versus gastric bypass surgery on ghrelin levels.
According to lead author David E. Cummings, M.D., the findings not only shed light on
what may be an underlying reason for the success of gastric bypass surgery, but raise the
possibility of a new generation of safer, more effective weight-loss drugs.
"If the absence of ghrelin contributes to the effectiveness of gastric bypass surgery, then
we may be able to achieve at least some of that weight loss by antagonizing [blocking]
ghrelin medically. If this approach works, then it might be something we could use even
for people who are only modestly overweight," said Cummings, an endocrinologist with
VA and UW. He added that researchers have yet to develop an antagonist, or molecular
blocker, for the hormone.
Currently available weight-loss drugs work mainly by raising levels of the serotonin and
norepinepherine (neurotransmitters), which can increase metabolism and reduce appetite
or by blocking the absorption of fat in the digestive tract. But many of these medications
have potentially serious side effects, such as hypertension. Two drugs – dexfenfluramine
and fenfluramine – were pulled from the market in 1997 after being linked to heart
damage. Fenfluramine had been used together with phentermine, the combination
popularly known as "fen-phen."
Gastric bypass surgery, according to conventional medical wisdom, works because it
dramatically reduces the portion of the stomach that is available to accept food. In the
operation, 95 percent of the stomach is sewn shut so it can't receive food. As a result, the
patient feels full much sooner and eats less at each meal. However the new study suggests
another mechanism may be at work. The research team believes the cells in the stomach
that produce ghrelin become inactive when they are no longer exposed to food in the gut.
"We think ghrelin cells 'go to sleep' when they're deprived of contact with ingested
nutrients," Cummings said.
To test the theory, the researchers analyzed blood samples from 13 obese patients before
and after a six-month low-fat, low-calorie diet, and from five patients who had undergone
gastric-bypass surgery within the past one to three years. Ten normal-weight patients
served as a control group. The dieters lost an average of 17 percent of their body weight,
and their ghrelin levels rose 24 percent.
The surgery group had lost an average of 36 percent of their weight, and their ghrelin
levels remarkably had sunk to 77 percent below normal, and 72 percent below the dieters'
level. The very low levels of the surgery group did not show the pre-meal increases and
post-meal decreases that were found in normal adults.
According to Cummings, the rise in ghrelin caused by dieting and several other forms of
weight loss is part of the body's normal adaptive response. When we lose weight, the
body senses this as famine, and triggers a survival mechanism to keep our weight
constant – the metabolism rate drops, and we feel hungrier, so we'll eat more. That's the
ostensible reason, notwithstanding the new findings on ghrelin, why most diets fail: Will
power can forestall the urge to eat more for only a limited time. Gastric-bypass surgery is
the only method known to short-circuit this normal body response, perhaps in part by
disabling ghrelin-producing cells.
Cummings now plans to study how gastroplasty, or stomach stapling, affects ghrelin.
That procedure has been shown in clinical trials to be less effective than gastric bypass
surgery, and its usage has declined as a result. Gastric bypass surgery, though not without
risks, is seeing a boom in popularity. It is recommended only for so-called "morbidly
obese" patients-those with a body mass index of 40 or more, or 35 or more with known
medical problems due to obesity.
"It's reasonable to wonder if the difference in efficacy between the two procedures arises
because one shuts off ghrelin and the other doesn't," said Cummings.