Many people make resolutions they want to practice in the New Year. One of the most common resolutions is to lose weight by eating healthy food and exercising regularly. However, it is difficult for ordinary people to achieve this goal without great determination and commitment.
Recently, a drug was developed to treat obesity, and celebrities bragged about the results, sending the developer’s stock price through the roof. The health consequences of obesity cannot be overstated. That’s because it goes far beyond how you look. So, it's only natural that people should be concerned about it.
There are different definitions of obesity, but it's usually based on BMI (body mass index), which is weight in kilograms/height in meters). The World Health Organization (WHO) defines obesity as a BMI of 30 kg/m2 or more, and the WHO’s Western Pacific Region defines obesity in Asians as a BMI of 25 kg/m2 or more.
There are many theories explaining the pathophysiological mechanisms of obesity. Obesity is highly genetic, and studies of twins show a 40-70 percent BMI concordance rate. There is also the so-called "set-point" theory, a rather pessimistic theory that suggests that obesity levels are fixed for each individual.
In addition to genetics, environmental factors, such as exercise, diet, and obesogenic substances, play a role in determining and changing this. While most obesity is caused by a combination of genetic and environmental factors, very rare genetic obesity diseases are caused by a single genetic abnormality. They are characterized by the onset of obesity at a young age and do not respond well to typical dietary and behavioral modifications.
A case in point is Prader-Willi syndrome, a rare disorder caused by a microdeletion in the proximal ileum of chromosome 15 on the father's side in about 75 percent of cases, which mostly occurs spontaneously. Monozygotic aneuploidy, in which two copies of chromosome 15, one from each parent, are inherited from the mother alone, accounts for the other 25 percent. The risk increases as the mother's age increases. The remaining rare causes are mutations in the imprinting process of the proximal part of the long arm of chromosome 15 or structural abnormalities, such as unbalanced translocations of chromosomes.
A newborn with Prader-Willi syndrome is drooping and has a weak cry. The skin is white, and the hair is brown. In the early days of life, the infant sucks poorly and shows no interest in eating. Facial features include a narrow forehead, almond-shaped eyes, a small, downturned, triangular-shaped mouth, a thin upper lip, a small chin, increased amounts of thick, sticky saliva, and small hands and feet. Boys also have a smaller penis or testicles and may have latent testicles.
Appetite increases at the age of two to three, characterized by excessive weight gain. Their constant craving for food also leads to food stealing, hiding behaviors, and grafting. They have obsessive-compulsive tendencies, picking at their skin to create scars, and they may have rage attacks and behavioral problems at the slightest frustration. They may also have trouble sleeping and apnea when they sleep.
In addition, many of the problems that appear in childhood persist into adulthood. Behavioral problems, learning disabilities, and rage attacks are some of the most common problems in teenagers. Hypogonadism is a condition in which the hypothalamus of the brain fails to produce gonadotropins, resulting in a dwarf penis and latent testicles.
Puberty may also be delayed or absent in both sexes. There are also cases of central adrenal insufficiency. Short stature and young bone age are common symptoms. Growth hormone treatment helps motor development by increasing muscle strength, even in patients without growth hormone deficiency. It increases energy expenditure, strengthens bone tissue, and reduces fat in the body. Therefore, growth hormone treatment is recommended for all patients because it has been shown to reduce weight, increase muscle mass, and increase height. The only caveats are if you have overt type-2 diabetes, sleep apnea, or severe scoliosis.
Growth hormone treatment does not improve behavioral problems or excessive food cravings. Several anti-obesity medications have been tested in people with Prader-Willi syndrome, but none are effective.
Currently, there are many research efforts underway to treat Prader-Willi syndrome. For example, a drug that inhibits the reuptake of three neurotransmitters in the brain has been developed and reported good results in phase I clinical trials.
Besides, there are many other rare diseases where obesity is a major problem. For instance, Bardet-Biedl syndrome is characterized not only by obesity but also by vision impairment due to cone dystrophy of the retina, polydactyly, cognitive impairment, hypogonadism, and genitourinary and renal malformations.
It is an autosomal recessive disorder that occurs in 25 percent of children born to parents who are carriers. This is a bit technical, but the melanocortin-4 receptor system in the brain plays a very important role in the center of appetite control. Many rare genetic disorders have been linked to this system. These are rare genetic diseases in which mutations in genes such as POMC, PCSK1, and LEPR cause morbid obesity. Fortunately, there is an obesity drug called setmelanotide, recently approved by the U.S. Food and Drug Administration (FDA).
Another condition is Alström syndrome. It is an autosomal recessive genetic disorder characterized by obesity, retinal damage, progressive sensorineural hearing loss, cardiomyopathy, type 2 diabetes mellitus, and nonalcoholic liver disease. Setmelanotide is not approved for this condition due to unclear efficacy.
Advances in genomics over the past decade have identified numerous genes involved in obesity, as well as very rare inherited obesity disorders. There is an active research effort to understand the pathophysiology of obesity and identify therapeutic targets. If a treatment for a rare genetic obesity disease is developed, it is possible that drug repositioning may be effective for common obesity.
Professor Yoo Han-wook graduated from Seoul National University College of Medicine and trained at the Center for Jewish Genetics at Mount Sinai Hospital in the United States from 1989 to 1992 before becoming a board-certified medical geneticist. He served as the director of the Medical Genetics Clinic at Asan Medical Center in Seoul and the Pediatric Hospital director. He is currently a professor of pediatrics at CHA University Bundang Women's Hospital. He has served as president of the Korean Society of Pediatric Endocrinology, chairman of the Korean Society of Medical Genetics and Genomics, director of the Center for Genomic Research on Congenital Malformations and Genetic Diseases at the Ministry of Health and Welfare, and chairman of the Planning Committee for the Conquering Rare and Difficult Diseases Project at the Korea Health Industry Development Institute.