Biology 202
2000 First Web Report
On Serendip

Many pharmaceutical companies are involved in the race for effective weight loss drugs. For example, dexfenfluramine, a drug that acts by raising the level of the neurotransmitter serotonin, increases satiety and produces a "feeling of well-being." (3)(4) Serotonin levels increase naturally when starch is ingested (starch is broken down into sugar, sugar causes the secretion of insulin by the pancreas, insulin leads to an increased amount of the amino acid tryptophan, a precursor to serotonin, in the brain). So, it is suggested that obese people eat carbohydrates in order to produce serotonin or, rather, its resulting feeling.(3)

While obesity compounds the risk of heart disease, stroke, diabetes, etc., it is not a major problem unless one is 40% or more above his or her ideal weight.(3) So,really, it is society that drives people to want to be slender. Some people are very obese because their body weight set point (partially genetically determined) is higher than average. It is neurotransmitters in the brain, though, that govern one's appetite and weight.(3)

Various studies have linked the neurotransmitter, neuropeptide Y (NPY), and protein, leptin, to important roles in the regulation of body weight and appetite and to interactions with each other. (1)(2)(5)(6)

Leptin-
In 1994, the gene "ob," whose protein product is leptin-- from the Greek leptos or "thin"--was found to be mutated in genetically obese mice (5). Leptin, normally produced by adipose tissue (by an unknown mechanism), is absent in these obese, hyperphagic mice because of the ob mutation. Studies have shown that when it is injected into the cerebral ventricle of ob/ob mice, their metabolic rate increases and they eat less, and, therefore, they lose weight(1)(5)(6). It is believed to act on the regions of the brain responsible for appetite and satiety through a negative feedback loop (1,6). Leptin moves through the blood stream and binds to high affinity receptors in the hypothalamus specific to feeding regulation(1)(6). That it acts through the central nervous system (rather than the peripheral one)is evident by the smaller dosage needed to decrease feeding when administered intracerebroventricularly. (6) Interestingly, a study on obese human subjects showed that they actually have higher concentrations of serum leptin (four times higher in most cases) and ob mRNA in adipocytes than normal people (5)(6). Explanations include a decreased leptin sensitivity in obese individuals (perhaps because of mutated leptin receptors or signal transduction problems) and a different, more complicated mechanism in humans that is not understood(6). Yet experiments have shown that, when administered in large doses, leptin does result in some weight loss in obese people(5).

It is thought that leptin acts in a negative feedback loop with glucocorticoids and insulin. When food is consumed, these are produced, fat is deposited, and then leptin is released and the animal feels satiated(6).

Neuropeptide Y-
If leptin is responsible in some way for satiety, what causes appetite? A study connected the inhibition of the expression of the neurotransmitter, NPY, to the injection of leptin in ob/ob mice. Neuropeptide Y, a 36 amino acid peptide amide-- its sequence is conserved in different species-- found all over the peripheral and central nervous systems, stimulates feeding. Subject to daily fluctuations related to circadian rhythm, it is at peak concentration just before dark.(2) Present in the neurons of the brain, cardiovascular system, gastrointestinal tract, and kidney, it apparently acts via the G protein-coupled receptors, Y1 through 5 (1). Its neurons are the ones most numerous in the heart and surrounding area, innervating them through a sympathetic pathway. It is also observed throughout the GI tract--as mentioned above-- released along with noradrenaline. There it serves a regulatory function in digestion and reabsorption, And, in the kidney it also plays a role in proper functioning. In the cerebral cortex and striatum, NPY neurons are also found. The possibility that it plays a part in mood is seen in its increased activity after anti-depression treatment and regulation of serotonin and noradrenaline secretion(1).

Returning to NPY's role in feeding, experiments have shown that its gene expression appears to be inhibited in the presence of leptin. So, when leptin is injected, NPY levels drop and the animal loses weight. It makes sense, therefore, that it plays an important role in the stimulation of eating (especially of carbohydrates). Specifically, feeding is stimulated by NPY neurons that originate in the arcuate nucleus and extend to the paraventricular nucleus in the brain (1). And this does not apply only to obese animals. When NPY is injected into the cerebral ventricles of normal ones, they also experience increased feeding and weight gain (6). NPY appears not only to stimulate feeding but also the secretion of insulin and glucocorticoids(leading to the accumulation of fat and obesity)(5)(6)

Experiments with Y5 subtype antagonists (these function to block the NPY receptors) have lead to some interesting findings. Rats were made to fast for 24 hours and, then, injected with either prepro NPY antisense oligodeoxynucleotides, scrambled oligodeoxynucleotides, or saline. After the 24 hour period, the animals were given food again. The ones treated with the prepro NPY antisense ODNs not only lacked any evidence of NPY synthesis (expected during fasting situations) but also the size and duration of their meals decreased and the interval between feeding times increased. The Y5 antisense ODNs worked by blocking the feeding control pathway of NPY ((1)).

In recent years, there have been many discoveries in the neurobiology of feeding. Obesity seems to be a result (on a basic level) of a combination of high levels of neuropeptide Y and low levels of leptin (or, at least, an inability to use the available leptin). Neuropeptide Y and leptin are obviously important in body weight regulation, however, there are additional substances that also have roles in thie and are yet undiscovered.

WWW Sources

2)From Food and the Circadian Activity of the Hypothalamic-pituitary-adrenal Axis,

3)Using Serotonin Reuptake Inhibitors for Weight Loss,

4)Other Drugs are Already in the Pipeline,

5)Leptin- Can Obese Mice Lead to Lean People,

6)Obesity, Leptin, and the Brain,

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