Histidyl-proline diketopiperazine is a cyclic dipeptide otherwise known as cyclo (HisPro) or CHP. CHP is a cyclic structure formed from the amino acids histidine and proline, and is a major metabolite of thyrotropinreleasing hormone (TRH). In addition to being a metabolite of TRH, it appears that CHP may be derived from sources other than TRH. Thus, CHP is found throughout the human body.
More specifically, CHP is found in the central nervous system, gastrointestinal tract, and a variety of body fluids including milk, blood, cerebrospinal fluid, and urine. CHP is also found in many foods including tuna, shrimp, and ham Some dietary supplements that contain casein or soy protein may also contain relatively large amounts of CHP. Research indicates that CHP exhibits a variety of biological functions including appetite suppression, a reduction of ethanol narcosis (CNS depression), a decrease in cholesterol synthesis, and an inhibition of insulin secretion. CHP is not yet a dietary supplement but does show promise in animal studies.
Animal Studies
A supplement that can increase satiety is probably altering the chemical signals within the hypothalamus because that is where the hunger center appears to be located. Studies have shown that CHP exhibits a neuromodulatory mechanism, which appears to be responsible for its satiety effect.
The first study reporting the anorectic role of CHP was conducted by Morley et al. Rats who received CHP ate 50-80% less food than control rats. The researchers postulated that the CHP was inhibiting dopamine uptake in nerve terminals thought to be responsible for feeding behavior The anorectic role of CHP has been supported by subsequent research. In two separate studies, CHP has been reported to reduce food intake by 20-50% in rats.
Although the exact mechanism of action for CHP is unknown, CHP has been hypothesized to act through a number of mechanisms such as dopamine, norepinephrine, and serotonin metabolism or even their transporters. In addition, CHP may act like gut peptides. Food in the GI tract may stimulate the release peptide hormones that reduce food intake. Circulating CHP has been shown to change following a glucose load. Plasma CHP showed a rise followed by a fall below baseline and then a recovery toward normal after an oral glucose load, but not after intravenous administration of glucose This pattern is similar to that reported in humans.
Human Studies
Descriptive research of CHP in humans indicates that endogenous CHP is distributed throughout the body and responds similarly to the CHP in rats. The role of CHP administration in humans is unknown due to the lack of research studies and to ethical considerations. More research is needed to investigate the safety of CHP before it can be administered to humans.
However, a few investigations have focused on the changes in endogenous CHP levels following the consumption of food by humans and in different human diseases as they related to food consumption. Steiner and coworkers investigated the relationship of endogenous CHP levels in patients with anorexia nervosa and bulimia. Anorexia is accompanied by an absence of hunger, which results in malnutrition. Bulimia, on the other hand, is associated with an inability to feel satiety even after massive food consumption.
Steiner reported that as anorexics lost weight their CHP levels actually increased. In fact, a 2-kg weight loss was associated with a 42% increase in CHP levels. This negative correlation between weight loss and CHP levels indicates that anorexics had less desire to eat with the more weight they lost. On the other hand, bulimics responded in just the opposite manner. As bulimics lost weight, CHP levels dropped as well, suggesting that bulimics experience an absence of satiety, increasing the likelihood of the binge eating and purging that is characteristic of this disease.
Currently, there are some plans to conduct fat-loss studies in adults. However, one of the problems the researchers are having is finding a manufacturer for CHP Small amounts can be purchased for animal studies, but the cost of this dipeptide makes it cost prohibitive to give to humans.
Another important item is that while a reduction in energy intake will result in weight loss, the weight loss may not be permanent. During a reduction in energy intake, metabolic rate will often decrease to compensate for this reduction in intake. This reduction in metabolic rate may be linked to a decrease in thyroid hormones. The decrease in metabolic rate will result in the negative caloric balance being offset, and may possibly result in a positive caloric balance, leading to an increase in body weight. This is why long-term weight loss cannot be achieved without exercise. Exercise helps maintain and even increase the metabolic rate.
Safety and Toxicity
The studies investigating the physiological effects of CHP administration have been careful to document any adverse reactions. Peters et al administered 400 micron g of CHP intravenously to humans and reported that throughout the study there were no subjective or abjective side effects of CHP administration. Animal studies have also verified that CHP administration has minimal or no negative side effects. Nevertheless, more human studies need to be performed. Exogenous CHP may alter a variety of endocrine and CNS-related activities including thermoregulation, pain responsiveness, inhibition of insulin release, and inhibition of prolactin.
Prolactin is a hormone released by the anterior pituitary gland. Many studies have reported that CHP may inhibit basal levels of prolactin and the amount secreted during suckling in women. In women, prolactin is responsible for milk production and let-down. Therefore, a decrease in prolactin may decrease milk production.
If CHP reaches the market as a dietary supplement, it should not be consumed by women who are breast feeding because it will appear in breast milk. Also, prolactin enhances testosterone production by a direct interaction with receptors on Leydig cells. Therefore, a decrease in prolactin may result in a decrease in testosterone production, which could alter protein synthesis and muscle mass, leading to a change in metabolic rate.
Since CHP may also decrease insulin release, athletes may find that both glycogen resynthesis and protein synthesis may be decreased. In male athletes, coupled with the possible decrease in testosterone, CHP may not be a supplement to consume because of the potential negative effects on muscle mass.
