Modern women are beautiful when they are thin. The best way to lose weight is to eat less and move more, but this seems too simple for group-level obesity, scientists believe that effective strategies for weight loss need to combine neuroscience, genetics and behavioral science, multi-faceted approach.
Recently, “Nature Outlook” (Nature Outlook) with the title “Obesity”, including obesity and genetics, obesity and the microbiome, obesity and neuroscience and other aspects of the research results. The article points out that for such a popular word, we do not understand in depth, although we know a lot about how to store and burn fat tissue, but why some people seem to be easy to gain weight? How does the so-called appetite work? And are changes in gut microbes a cause or a consequence of obesity? These are all unanswered questions.
Obesity and genetics
Two geneticists from Cambridge University: Stephen O’Rahilly and Sadaf Farooqi have been working on obesity-related genes for fifteen years, and their first major breakthrough came in 1997 when a pair of severely obese cousins from Pakistan were referred to them for clinical evaluation.
The eight-year-old girl weighed 86 kilograms, which is comparable to the weight of a tall man, and the other ten-year-old boy weighed 115 kilograms. They felt hungry no matter how much they ate.
O’Rahilly and Farooqi gave them a rapid blood analysis, and found that both children lacked leptin (leptin): a hormone that regulates appetite, and the scientists found that the cousins had a mutation in the gene that generates leptin, the ob gene, which was only recently discovered.
This is the first time it has indeed been proven that our genes cause obesity.
”Obesity is one of the strongest genetically influenced shapes that we humans have,” O’Rahilly said. Classic twin experiments conducted in the 1980s and 1990s showed that 40C70 percent of the difference in body size was due to genetic factors.
Over the years, a number of obesity genes have been identified, such as the FTO gene, and scientists believe that mutations in the FTO gene are one of the strongest genetic determinants of obesity risk in humans, and in order to understand the link between the two, researchers have conducted extensive research on intron mutations in the FTO gene.
This year, researchers from the University of Chicago and others have made important achievements in this area, mapping the behavior of a number of promoters positioned within a million base pairs on either side of the FTO gene. In adult mouse brains, the researchers found that the promoters that turn on the FTO did not interact with the obesity-associated FTO introns. Using data from 135 brain samples from individuals of European ancestry, they found that mutations in FTO introns that affect body weight were associated with IRX3 expression, but not with FTO self-expression. The obesity-associated FTO intron acts as a regulatory element to enhance IRX3 expression, and the FTO gene itself does not appear to play a role in this interaction.
To verify the role of IRX3, the researchers constructed engineered mice lacking the IRX3 gene. These mice were significantly thinner compared to their normal counterparts. They were about 30 percent lighter, mainly due to reduced fat.
The weight loss occurred despite normal levels of food intake and physical activity. When fed a high-fat diet, mice deficient in IRX3 maintained the same weight and fat levels as on a normal diet. Normal mice fed the high-fat diet gained nearly 2-fold in body weight. the IRX3-deficient mice had smaller adipocytes and increased levels of brown fat were observed. In addition, these mice were better able to process glucose.
This study suggests that some obesity-related elements within FTO interact with the distal gene IRX3, which appears to be a functional obesity gene. the FTO gene itself appears to have only peripheral effects on obesity.
In addition to genetic influences in the genome, epigenetic inheritance also contributes to the inheritance of obesity, and although there is little evidence from studies on the risk of obesity across epigenetic inheritance, some scientists have found an association, such as Washington State University epigeneticist Michael
Skinner, for example, found that exposure of pregnant rats to a number of pollutants caused their offspring’s offspring to become obese, and the researchers demonstrated that this epigenetic alteration was seen in sperm.
This study cannot be replicated in humans, but it does help us to gain a deeper understanding of our health, and the health of the next generation.
Obesity and the microbiome
A few years ago, Professor Liping Zhao, a microbiologist from Shanghai Jiao Tong University, helped a patient with a BMI of 58.8, a level of BMI that indicates extreme obesity, and after 6 months of treatment, the patient lost over 50 kg and a bacterium called Enterobacter had been found in his stool samples after This bacterium occupied 35% of this patient’s intestinal tract.
The reduction in these bacteria may not seem as impressive as this patient’s weight loss, but Professor Zhao and many other researchers believe that the human intestinal flora, the approximately 1,000 species of bacteria in our digestive tract, is significant in regulating body weight.
Determining whether a person is obese “is not just about calories,” says Prof. Zhao, adding that in order to lose weight, “the nutritional requirements of the beneficial bacteria in the lower digestive tract also need to be taken into account.” Likewise, a healthy diet can stop obesity.
Professor Liping Zhao has previously identified a type of intestinal bacteria called Enterobacter cloacae as one of the culprits of obesity. The researchers found that this bacterium was present in large numbers in the intestines of morbidly obese human volunteers. The researchers then injected the bacterium into mice that would not have gained weight on a high-fat diet for up to 10 weeks and found that when given a rich diet, the mice became overweight. It also caused inflammation and insulin resistance in the mice, and also turned off genes needed to burn fat and activated genes needed to synthesize fat.
And in one clinical trial, a patient was put on a food regimen that led to a weight loss of more than 30 kilograms after nine weeks and a reduction in the presence of Enterobacter cloacae in the patient’s gut to “undetectable” levels.
As microbiome research progresses, the link between these microbes and obesity is becoming clearer, and last year an international team of researchers led by the French Institute of Agricultural Sciences (INRA) used advanced DNA analysis and bioinformatics methods to map the human gut flora.
This study pointed out that the lower the number and diversity of intestinal flora, the more obese people are than others. Flora with the potential to cause mild inflammation in the digestive tract and throughout the body predominated in their bodies. The blood samples reflected this, revealing that these people were in a state of chronic inflammation. We know from other studies that this chronic inflammatory state affects metabolism and raises the risk of type 2 diabetes and cardiovascular disease.
Obesity and Neuroscience
Many people believe that overeating is caused by a lack of willpower, but feeding behavior is actually regulated by extremely strong biology, as recognized by neuroscientist Bradford Lowell from Beth Israel Deaconess Medical Center back in the 1970s, when he scratched i small wounds on the brains of rats in hopes of finding brain regions associated with obesity. After these animals began to overeat and became very obese, Lowell was “surprised to find that such a small lesion could have such a huge effect.”
Thirty years ago, there were few ways to study this mechanism in the brain, and it was only through Lowell’s wound approach, but by 1989, the development of mouse knockout technology, as well as Cre/lox conditional knockout technology, gave scientists a deeper understanding of neuronal function, and in the last few years optogenetics and chemogenetics methods have helped to study neural circuits that regulate feeding.
In addition, the biological clock is also closely related to obesity, and one study pointed out that an important signaling system in the brain controls appetite, energy expenditure and body fat composition. One of these specific genes determines how fat or thin the body is.
In the human brain, the neurotransmitter NPY acts on four well-known cell surface receptors (Y1, Y2, Y4 and Y5) to trigger the effects of the NPY system. In the mouse brain, there is also a role for receptor Y6, which is produced in a small region of the brain responsible for regulating the biological clock and the production of growth hormone. This new study shows that the Y6 receptor has a profound effect on the body fat composition of mice.
The researchers found that the Y6 gene is highly expressed in the supraoptic nucleus of the hypothalamus, a region that controls the body’s circadian rhythm and also tightly regulates the metabolic process of food. In addition, the Y6 gene promotes high levels of expression of specific peptides, including vasoactive intestinal peptide (VIP), which controls the release of growth hormone.