invent a diet pill.

First you have to choose what kind of pill you want to

invent. Is it for treating obesity or maybe for increasing energy intake or
something else? Describe your goal briefly and go through the basic
mechanisms the effect of the pill would be based on. Also point out what
the anticipated result should be. Your work should be based on the
articles linked to here

-The role of leptin and ghrelin in the regulation of food intake and
body weight in humans: a review

Abstract:

Leptin and ghrelin have a major influence on energy balance.

Leptin is a mediator of long-term regulation of energy balance,
suppressing food intake and thereby inducing weight loss.
Ghrelin is a fast-acting hormone, playing a role in meal initiation.

In obese subjects circulating level of anorexigenic leptin is increased,

whereas surprisingly the level of orexigenic ghrelin is decreased.
 It is now established that obese patients are leptin-resistant

Introduction:

To have a constant weight, there must be an energy balance. A growing

number of people nervertheless suffer from obesity.
Body weight is regulated by a complex system, including both peripheral
and central factors. Two of the hormones that play an important role in the
regulation of food intake and body weight are leptin and ghrelin.

Both originate in the periphery and signal through different pathways to

the brain, particularly to the hypothalamus.
In the hypothalamus, activation of the leptin or ghrelin receptor initiates
different signalling cascades leading to changes in food intake.

Botht the leptin and ghrelin systems are disturbed in obesity, it is

important to understand both systems to develop therapeutics.

Leptin is a hormone produced mainly by adipose tissue:

OB gene and product leptin. In addition to adipose tissue, leptin is also

produced in small amounts in other human tissues (stomach, mammary
epithelium, placenta and heart).

Leptin acts through the leptin receptor (LEPR or OBR). One of the OBR
variants, OB-Rb is widely expressed in the brain. OB-Rb is highly
expressed in the hypothalamus and cerebellum.

Leptin is released into the circulatory system by the adipose tissue as

a function of the energy stores.
  Serum, plasma, and CSF leptin levels are higher in fat individuals
 Plasma leptin can cross the BBB
After release from the adipose tissue, leptin signals the brain about the
status of the body energy stores.

Leptin´s role in energy balance is mediated through the

hypothalamus:

Leptin has a role in various biological mechanisms, including as a

feedback mechanism that signals to key regulatory centres in the
brain to inhibit food intake and regulate body weight and energy
homeostasis.
Studies in rodents have shown that the hypothalamus is the primary
centre for regulation of food intake and body weight.

After leptin is released from the adipose tissue to the bloodstream, it

crosses the BBB and binds to hypothalamic leptin receptors,
influencing the activity of various hypothalamic neurones and the
expressoin of various orexigenic and anorexigenic neuropeptides.

Orexigenic and anorexigenic peptides play an essential role regulating

appetite and energy balance by modulating the activity of neurons in the
hypothalamus. Ghrelin is an orexigenic released during fasting.

Orexigenic peptides, influenced by leptin, include neuropeptide Y

(NPY), melanin concentrating hormone, agouti-like peptide
(AgrB), galanin, orexin and galanin-like peptide (GALP).
One of the most important mechanism by which leptin controls food
intake is by regulating the effects of ghrelin (ghrelin blocks leptin´s
action through the activation of hypothalamic NPY/Y1 receptor pathway).
But is is still a possibility that leptin is not an upstream regulator of
ghrelin.

Anorexigenic peptids, influenced by leptin, include POMC, cocaine-

and amphetamine-regulated transcript, neurotensin, CRH and
BDNF.

The orexigenic and anorexigenic neurons are located in various

hypothalamical regions (arcuate nucleus (ARC), lateral
hypothalamus, perifornical hypothalamus and parventricular
nucleus)
Leptin induces weight loss by suppression of food intake and by
stimulation of metabolic rate:

Mutation in OB gene (leptin gene) in children led to normal birth weight

but rapid development of severe obesity from over-eating and impaired
satiety. Leptin treatment results in decreases apettite, weight loss,
increased physical activity, changes in endocrine function and
metabolism.

Leptin is produced not only by adipose tissue, but also in small amount in
stomach. Hence, it has been suggested that leptin may play a role in the
control of meal size in cooperation with other satiety peptides.

Has been shown that several intestinal peptides induce gastric leptin
release.
Also, gastric leptin secretion is stimulated by insulin
administration, which is normally released after eating.

Possibility leptin role in adaptation to energy deprivation. Shown

reduced leptin levels during fasting, not associated with decrease in
adipose mass. Disease states like exercise-induced amenorrhoea and
anorexia nervosa also associated with low leptin concentration and
neuroendocrine functioning.
Ghrelin is a hormone secreted by the stomach:

GHRL gene. Ghrelin is primarily produced in the stomach, but also been
found in GI tract, pancreas, ovary and adrenal cortex.
In the brain, ghrelin-producing neurones identified in the pituitary,
hypothalamic ARC, group of neurones in hypothalamus.

Ghrelin binds to the growth hormone secretagogue receptor (GHS-

R), GHS-R1a and GHS-R1b.

Secretion of ghrelin by the stomach largely depends on the

nutriotional state.
 Ghrelin levels show preprandial increases and postprandial
decreases.
 Ghrelin levels shows diurnal variation

Leptin has been suggested to have incluenced on circulatin ghrelin.

Hypothesis is that leptin satiety-inducing effects come from
suppression of ghrelin secretion, shown to be a ghrelin upregulator
in rodents, but conflicting results in humans.

The role of ghrelin in food intake is mediated through the

hypothalamus:

1. After release fro the stomach to the bloodstream, crosses the

BBB and binds hypothalamus receptors.
2. May reach the brain through the vagal nerve.
3. Ghreli produced locally in the hypothalamus, where it may
directly affect the hypothalamic nuclei.

Ghrelin attenuates leptin-induced reduction in food intake and

body weight by modulating the expression of various
hypothalamic peptides.
Ghrelin stimulates the activity of neurones expressing NPY, AgRP,
and orexin.
Ghrelin has inhibitory effect over POMC, CRH-producing neurones.
Ghrelin appears not to be a direct regulator of leptin.

Ghrelin presumably functions as an appetite-stimulatory signal:

Ghrelin regulates secretion of GH by the pituitary.

Also has effect over GI tract, immune cell activation and
inflammation.
Demonstrated tht the preprandial increase in ghrelin levels correlates with
hunger scores in healthy humans, initiating meals voluntarily in the
absence of time- and food-related cues.

IV infusion of ghrelin induces hunger and food intake among

healthy and obese individuals. Indicating that ghrelin functions as a
meal-initiating signal, mediated by through its stimulatory effect on
gastric emptying (demonstrated in humans).

Ghrelin may have short-term regulation on food intake and also a

role in long-term regulation of energy balance. Peripheral daily
administration of ghrelin induces adiposity in rodents by reducing
fat utilization.

In addition, circulating ghrelin concentration are negatively correlated with

BMI, and levels increase when obese humans lose weight, and decrease
when anorexia nervosa patients gain weight. Suggesting that ghrelin
levels change in response to dieting to maintain body weight.

Ghrelin does not seem to be crucial for the maintenance of

energy homeostasis. Ghrelin KO mice have normal body size,
body composition, bone density, growth rate, gastric emptying,
good intake, reproduction,…
Moreover, Ghsr-null mice havea normal appetite, show a normal body size,
body compo-sition, body weight and bone density, and show normalserum
leptin and insulin responses to fasting. However, body weights of mature
Ghsr-null mice were modestlyr educed, which might be related to ghrelin’s
role in GH release, resulting in subtle changes in body composition.
Together this indicates that ghrelin is not critically requiredfor growth,
appetite and fat deposition, and is not likely tobe a direct regulator of
leptin and insulin.

Do abnormalities in leptin and ghrelin or their actions contribute

to the development or maintenance of obesity:

Suprinsingly leptin levels increased in obese individuals and

ghrelin decreased.

As obese humans show elevated levels of leptin in serum and adipocytes,

and show limited effects with leptin treatment, many researchers suggest
obese humans to be leptin-resistant. Over-eating exposure of the
hypothalamus to high leptin levels may have damaging effects on the
hypothalamus. As a result, the hypothalamus becomes less sensitive
to leptin, leading to a sustained increase in leptin levels.
Other hypothesis is deficient leptin transport across the BBB.

The potential of leptin and ghrelin as a drug target for weight

regulation:
Leptin as a Target
 Leptin treatment is effective in leptin-deficient patients but
not in most obese individuals due to leptin resistance.
 Alternatives to normal leptin function:
o Fc-leptin immunofusins: Extended half-life, effective in non-
leptin-deficient mice.
o Leptin administration post-weight loss: Prevents weight
regain and metabolic adaptations.

Ghrelin as a Target
 Ghrelin increases during weight loss, leading to weight
regain.
 Potential ghrelin-targeting strategies:
o Anti-ghrelin antibodies: Block ghrelin-induced food intake.
o GHS-R (Ghrelin Receptor) antagonists: Reduce hunger
set-point, lower food intake, and prevent weight gain.
o Caution: Possible involvement of other ghrelin-related
receptors in weight gain (e.g., beyond GHS-R1a).
 Targeting ghrelin signaling:
o Stimulating inhibitors of ghrelin signaling may suppress
appetite and weight gain.

It has been shown tha circulating ghrelin levels increase when obese
humans lose weight, and because obese mice show an increase in
sensitivity to ghrelin upon weight loss, blockage of ghrelin could
prevent weight regain after weight loss.

Conclusion:

Leptin is primarily involved in long-term regulation of energy

balance; it is released into the circulatory system as a function of
energy stores.

Whereas ghrelin is a fast-acting hormone, of which the circulatory

levels show clear meal-related changes. One other difference is that, in
contrast to leptin, ghrelin does not seem to be critical for normal
appetite and growth.

Obese patients are leptin-resistant, andit is therefore necessary to

develop a treatment that over-comes leptin insensitivity.

When obese patients lose weight, ghrelin levels show an increase,

as if to compensate for this weigh loss. Seems interesting to try ghrelin
antagonists while following a strict diet.

The peptides downstream of leptin and ghrelin constitute possible

targets for therapeutic interventions.