Scientists Finding Anti-Obesity Drugs With Fewer Side Effects

Fen-phen was once regarded as a miracle weight-loss drug, but when it induced heart valve lesions and mother life-threatening side effects, it was taken off the market. UT Southwestern Medical Center scientists are exploring Fen-phen’s behavior in the brain so that safer anti-obesity drugs with less side effects can be developed.

In a recent study, the researchers define a circuit in the brain that explains the ways fenfluramine, a component of Fen-phen, suppresses appetite.

“Our findings provide evidence that the neural circuit we’ve proposed is sufficient for the neurotransmitter serotonin to regulate food intake and body weight, ” said Dr. Joel Elmquist, professor of internal medicine and pharmacology at UT Southwestern and senior author of the study. “Fen-phen works directly on this pathway. Unfortunately, that drug also adversely affects peripheral tissue such as the heart.”

Mice were engineered for the current study, in which the expression of a serotonin receptor called 5-hydroxytryptamine 2C was blocked throughout the entire body. Previously, this produced obese mice resistant to the anorexic actions of fenfluramine. When activated by serotonin, however, this receptor is also known to suppress appetite. Using this mouse model, the authors engineered another set of mice in which the same serotonin receptor was blocked everywhere in the body except within a group of brain cells called pro-opiomelanocortin, or POMC, neurons. The POMC neurons, which are found in the hypothalamus, are also known to play an important role in suppressing appetite and inducing weight loss.

The scientists noted that the animals with no serotonin 2c receptors expectedly developed obesity as well as other metabolism disorders such as increased food intake, hyperactivity and leptin insensitivity. They also were prone to spontaneous seizures, said Dr. Elmquist. The mice in which the serotonin receptor was fre-expressed and functioning only in the POMC neurons stayed slim and responded to fenfluramine.

“The POMC-specific reactivation of the receptor only in POMC neurons normalizes the abnormal metabolism in these mice,” Dr. Elmquist said. “The animals don’t eat excessively. Their hyperactivity is also gone.”

Previous work from the UT Southwestern group led to the hypothesis that Fen-phen worked by activating the serotonin 2c receptor in the POMC neurons in the hypothalamus. The current work provides genetic proof supporting this model.

“Conventional wisdom is that fenfluramine increases serotonin release that then activates serotonin receptors in the brain to regulate food intake and body weight, but unfortunately, this drug also causes lesions in heart valves,” he said. “If you could develop a drug that would travel to both the brain and the peripheral tissues, and then give a blocker to protect the heart, it’s possible that you could prevent the harmful side effects and still aid weight loss. Admittedly, that’s a bit farfetched, but this mouse model could be used to test that theory.”

The team’s next step is to determine whether they’ve identified the sole circuit required to suppress appetite and induce weight loss.

Source: Neuron,

Comments

  1. quiact says

    The Consequences Of Obesity

    Obesity has been defined as when excess body fat accumulates in one to where their physical overgrowth makes the person unhealthy to varying degrees. Obesity is different than being overweight, as others determine obesity to be of a more serious concern.
    As measured by one’s body mass index (BMI), one’s BMI of 25 to 30 kg/m is considered overweight. If their BMI is 30 to 35 kg/m, they are class I obese, 35 to 40 BMI would be class II obese, and any BMI above 40 is class III obesity.
    Presently, with obesity affecting children progressively more, the issue of obesity has become a serious public health concern.
    Approximately half of all children under the age of 12 are either obese are overweight. About twenty percent of children ages 2 to 5 years old are either obese are overweight. The consequences of these stats on our children are very concerning, considering the health issues they may or likely experience as they get older.
    Worldwide, nearly one and a half billion people are either obese or overweight. In the United States, about one third of adults are either obese or overweight.
    Women of low socioeconomic status are likely to be twice as obese compared with those who are not at this status. It is now predicted that, for the first time in about 150 years, our life expectancy is suppose to decline because primarily of this obesity problem.
    Morbid obesity is defined as one who has a body mass index of 30 kg/m or greater, and this surgery, along with the three other types of surgery for morbid obesity, should be considered a last resort after all other methods to reduce the patient’s weight have chronically failed. Morbid obesity greatly affects the health of the patient in a very negative way. It has about 10 co-morbidities that can develop if the situation is not corrected. Some if not most of these co-morbidities are life-threatening.
    One solution beneficial in many cases of morbid obesity if one’s obesity is not eventually controlled or corrected is what is known as gastric bypass surgery. This is a type of bariatric surgery that essentially reduces the volume of the human stomach in order to correct and treat morbid obesity by surgical re-construction of the stomach and small intestine.
    Patients for such surgeries are those with a BMI of greater than 40, or a BMI greater than 35 if the patient has co-morbidities aside from obesity. This surgery should be considered for the severely obese when other treatment options have failed. The standard of care illustrating as to whether this surgery is reasonable and necessary should be clarified.
    There are three surgical variations of gastric bypass surgery, and one is chosen by the surgeon based on their experience and success from the variation they will utilize. Generally, these surgeries are procedures related to gastric restrictive operations or mal-absorptive operations.
    Over 200,000 gastric bypass surgeries are performed each year, and this surgery being performed continues to progress as a suitable option for the morbidly obese. There is evidence that this surgery is particularly beneficial for those obese patients that have non-insulin dependent Diabetes Mellitus as well.
    It is believed that the results of this surgery to correct morbid obesity greatly limits or prevents such co-morbidities associated with those who are obese. Yet about two percent of those who undergo this surgery die as a result from about a half a dozen complications that could occur. However, the surgery reduces the overall mortality of the patient by 40 percent or so, yet this percentage is debatable due to conflicting clinical studies at times.
    Age of the patient should be taken into consideration, as to whether or not the risks of this surgery outweigh any potential benefits for the patient who may have existing co-morbidities that have already caused physiological damage to the patient. Also what should be determined by the surgeon is the amount of safety, effectiveness, and rationale for a particular patient regarding those patients who are elderly, for example.
    Many feel bariatric surgery such as this should be considered as a last resort when exercise and diet have failed for a great length of time.
    If a person or a doctor is considering this type of surgery, there is a website dedicated to bariatric surgery, which is: http://www.asmbs.org,

    Dan Abshear

  2. quiact says

    The Potential Results Of Obesity

    Obesity has been defined as when excess body fat accumulates in one to where their physical overgrowth makes the person unhealthy to varying degrees. Obesity is different than being overweight, as others determine obesity to be of a more serious concern. While obesity is not a disease, it is a serious health risk for one who has this risk.
    As measured by one’s body mass index (BMI), one’s BMI of 25 to 30 kg/m is considered overweight. If their BMI is 30 to 35 kg/m, they are class I obese, 35 to 40 BMI would be class II obese, and any BMI above 40 is class III obesity.
    Presently, with obesity affecting children progressively more, the issue of obesity has become a serious public health concern. In the United States, greater than one third of all citizens are obese, and this number continues to progress.
    Approximately half of all children under the age of 12 are either obese are overweight. About twenty percent of children ages 2 to 5 years old are either obese are overweight. The consequences of these stats on our children are very concerning, considering the health issues they may or likely experience as they get older.
    Worldwide, nearly one and a half billion people are either obese or overweight. In the United States, about one third of adults are either obese or overweight.
    Women of low socioeconomic status are likely to be twice as obese compared with those who are not at this status. It is now predicted that, for the first time in about 150 years, our life expectancy is suppose to decline because primarily of this obesity problem.
    Morbid obesity is defined as one who has a body mass index of 30 kg/m or greater, and this surgery, along with the three other types of surgery for morbid obesity, should be considered a last resort after all other methods to reduce the patient’s weight have chronically failed.
    Morbid obesity greatly affects the health of the patient in a very negative way. It has about 10 co-morbidities that can develop if the situation is not corrected. Some if not most of these co-morbidities are life-threatening.
    One solution beneficial in many cases of morbid obesity if one’s obesity is not eventually controlled or corrected is what is known as gastric bypass surgery. This is a type of bariatric surgery that essentially reduces the volume of the human stomach in order to correct and treat morbid obesity by surgical re-construction of the stomach and small intestine.
    Patients for such surgeries are those with a BMI of greater than 40, or a BMI greater than 35 if the patient has co-morbidities aside from obesity. This surgery should be considered for the severely obese when other treatment options have failed. The standard of care illustrating as to whether this surgery is reasonable and necessary should be clarified.
    There are three surgical variations of gastric bypass surgery, and one is chosen by the surgeon based on their experience and success from the variation they will utilize. Generally, these surgeries are procedures related to gastric restrictive operations or mal-absorptive operations.
    Over 200,000 gastric bypass surgeries are performed each year, and this surgery being performed continues to progress as a suitable option for the morbidly obese. There is evidence that this surgery is particularly beneficial for those obese patients that have non-insulin dependent Diabetes Mellitus as well.
    It is believed that the results of this surgery to correct morbid obesity greatly limits or prevents such co-morbidities associated with those who are obese. Yet about two percent of those who undergo this surgery die as a result from about a half a dozen complications that could occur. However, the surgery reduces the overall mortality of the patient by 40 percent or so, yet this percentage is debatable due to conflicting clinical studies at times.
    Age of the patient should be taken into consideration, as to whether or not the risks of this surgery outweigh any potential benefits for the patient who may have existing co-morbidities that have already caused physiological damage to the patient. Also what should be determined by the surgeon is the amount of safety, effectiveness, and rationale for a particular patient regarding those patients who are elderly, for example.
    Many feel bariatric surgery such as this should be considered as a last resort when exercise and diet have failed for a great length of time.
    If a person or a doctor is considering this type of surgery, there is a website dedicated to bariatric surgery, which is: http://www.asmbs.org,

    Dan Abshear

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