L’obesity It is a complicated condition, caused by a combination of genetics, food environment, behavior, and other factors. For millennia, getting enough food to survive and thrive was difficult. For most people, it is now as easy as opening a refrigerator.
SH2B1 Gene Linked to Obesity
A gene called SH2B1 has been shown to play an important role in regulating food intake. SH2B1 mutations in humans are associated with obesity, type 2 diabetes, and metabolic-associated fatty liver disease, formerly known as nonalcoholic fatty liver disease.
“This gene controls eating and energy expenditure. Obesity is caused by two opposing axes: If you eat too much, you store fat. If you expend too little energy, fat stores,” said Liangyou Rui, Ph.D., Department of Molecular & Integrative Physiology and Elizabeth Weiser Caswell Diabetes Institute at the UM Medical School.
A study by Rui and his team has identified where this gene acts within the brain, an area called the paraventricular hypothalamus, or PVH, which is involved in regulating blood pressure and fluid balance. The findings are published in the journal Advanced Science.
Additionally, the team found that SH2B1-expressing neurons form a circuit, communicating with downstream neurons in an area known as the dorsal raphe nucleus, located in the brainstem. This area is involved in energy balance, body weight maintenance, and emotionally motivated behaviors. Stimulation of this circuit suppresses appetite in mice. In contrast, silencing SH2B1-expressing neurons in the PVH leads to obesity.
The team also uncovered the molecular mechanism behind how SH2B1 helps maintain weight, in part by enhancing BDNF/TrkB signaling, which promotes brain growth during development and, in a mature brain, maintains brain health. When this signaling goes awry, obesity and metabolic disease develop.
One theory, Rui notes, is that the inflammation associated with weight gain may negatively impact this pathway indirectly, by weakening the signals that tell you to stop eating. “We know that SH2B1’s action is important, because it’s highly conserved across species, from fruit flies to humans,” Rui says. “It functions as a kind of universal currency, not only enhancing cell signaling, but also the hormones leptin and insulin, which help regulate appetite and metabolism.”
Furthermore, no side effects resulting from the increase in SH2B have been identified so far, unlike currently widely used drugs, such as Ozempic or Mounjaro, which activate GLP-1 receptors. According to Rui, “If we can find a way to improve SH2B activity, we could have great potential in the treatment of obesity and obesity-related diseases.”
Grb10 protein offers potential approach for obesity treatment
For many people, maintaining a healthy body weight can be a challenge. According to the Centers for Disease Control and Prevention, among adults aged 20 and older, the prevalence of obesity is 42% in the United States. Obesity-related conditions, including heart disease, stroke, type 2 diabetes, and certain cancers, are among the leading causes of preventable premature death.
Seeking strategies to help people reach and maintain a healthy weight, researchers at Baylor College of Medicine, Second Xiangya Hospital of Central South University-China, and the University of Texas Health Science Center at San Antonio studied how the activity of the hormone leptin, which is involved in controlling appetite and energy expenditure, is regulated.
Working with mouse models, the team found that the Grb10 protein promotes leptin activity in the brain, opening the possibility of developing new Grb10-based approaches to treat obesity. The study appears in Nature Metabolism.
One way the body controls its weight is with leptin, which is produced by adipose tissue. The more adipose tissue the body has, the more leptin it produces. Leptin travels to the brain, where it informs specialized neurons of the amount of fat stored in the body. Large amounts of leptin tell the brain that there is a lot of fat storage. In response, the brain triggers behaviors that suppress appetite and increase energy expenditure, which leads to a reduction in adipose tissue and weight loss. When everything works well, this leptin-mediated feedback loop between adipose tissue and the brain results in a healthy, long-lasting body weight.
“Leptin’s ability to prevent excessive body weight gain by simultaneously suppressing appetite and increasing energy expenditure has made it a promising therapeutic approach to treat obesity,” said co-corresponding author Dr. Yong Xu, professor of pediatrics, nutrition, and molecular and cellular biology at Baylor.
“Unfortunately, leptin supplementation strategies have often proven ineffective in most cases of diet-induced obesity, in part due to the development of leptin resistance, a state in which circulating leptin levels remain elevated but fail to suppress food intake and body weight gain.”
In the current study, Xu and his colleagues looked for molecules that regulate leptin activity and could potentially be used to overcome leptin resistance. The team found that the protein Grb10 is a novel regulator of leptin activity.
“We found that Grb10 promotes leptin activity,” Xu said. “One feature of Grb10 that distinguishes it from previously discovered leptin regulators is its mode of action. Grb10 binds directly to the leptin receptor on neurons, forming a complex. The binding enhances leptin signaling and helps reduce food intake and increase energy expenditure. Other regulators do not bind to the leptin receptor but to other downstream molecules.”
After knocking out Grb10 in leptin-sensing neurons in the brains of mice, the animals ate more or reduced energy expenditure and gained weight. Increasing Grb10, on the other hand, had beneficial effects: it helped the animals reduce food intake, increase energy expenditure, and lose weight.
“These findings suggest that enhancing Grb10 activity may provide a means to increase leptin signaling and aid weight loss,” Xu said. “Our findings support further investigation into the possibility of developing a Grb10-based treatment for obesity.”
In the future, the team is interested in further investigating the mechanism of action of Grb10 in the brain. “Leptin can also regulate mood and other emotional states,” Xu said. “We want to know whether Grb10 is involved in mood regulation via interaction with the leptin receptor.”
Rare genetic variants that confer up to 6 times greater risk of obesity
A study led by researchers at the Medical Research Council (MRC) has identified genetic variants in two genes that have some of the most significant impacts on obesity risk discovered so far.
The discovery of rare variants in the BSN and APBA1 genes are some of the first obesity-related genes identified, for which the increased risk of obesity is not observed until adulthood.
The study, published in Nature Genetics, was led by researchers from the MRC Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge. The researchers used UK Biobank data and other data to perform whole-exome sequencing of body mass index (BMI) in more than 500,000 individuals.
They found that genetic variants in the BSN gene, also known as Bassoon, can increase the risk of obesity by up to six-fold and have also been associated with an increased risk of non-alcoholic fatty liver disease and type 2 diabetes. Variants in the Bassoon gene were found to affect 1 in 6,500 adults, which could therefore affect around 10,000 people in the UK.
Obesity is a major public health problem as it is a significant risk factor for other serious diseases, including cardiovascular disease and type 2 diabetes; however, the genetic reasons why some people are more prone to gaining weight are not fully understood.
Previous research has identified several genetic variants associated with obesity that confer significant effects from childhood, acting through the leptin-melanocortin pathway in the brain, which plays a critical role in regulating appetite.
However, while both BSN and APBA1 encode proteins found in the brain, they are not currently known to be involved in the leptin-melanocortin pathway. Furthermore, unlike previously identified obesity genes, variants in BSN and APBA1 are not associated with childhood obesity.
This led researchers to believe they had discovered a new biological mechanism for obesity, different from those already known for previously identified genetic variants of obesity.
Based on published research and laboratory studies reported in this article, which indicate that BSN and APBA1 play a role in transmitting signals between brain cells, the researchers suggest that age-related neurodegeneration may affect appetite control.
Professor John Perry, lead author of the study and an MRC research fellow at the University of Cambridge, said: “These findings are another example of the power of large-scale genetic studies of human populations to improve our understanding of the biological basis of disease. The genetic variants we identify in BSN confer some of the largest effects on obesity, type 2 diabetes and fatty liver disease seen to date, and highlight a new biological mechanism that regulates appetite control.”
The accessibility of large-scale databases such as the UK Biobank has allowed researchers to search for rare genetic variants that may be responsible for diseases including obesity.
For this study, the researchers worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico. This is important because the researchers can now apply their findings beyond individuals of European descent.
If researchers can better understand the neural biology of obesity, they may discover new potential drug targets for obesity treatment in the future.
Dr Slavé Petrovski, Vice President of the Center for Genomics Research at AstraZeneca, said: “Rigorous, large-scale studies like this are accelerating the pace at which we uncover new insights into the biology of human disease.
By collaborating across academia and industry, leveraging global datasets for validation, and incorporating a genomic approach into medicine more broadly, we will continue to advance our understanding of disease, to the benefit of patients.”
Professor Giles Yeo, lead author of the study from the MRC Metabolic Diseases Unit, added: “We have identified two genes with variants that have the most profound impact on obesity risk at a population level that we have ever seen, but perhaps more importantly, that the variation in Bassoon is linked to adult onset rather than childhood obesity. So these findings give us a new understanding of the relationship between genetics, neurodevelopment and obesity.”
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