Can the lack of a single gene cause obesity?

The SMIM1 gene has been identified as a potential new factor in genetic predisposition to obesity. This discovery was made by an international team of scientists investigating the genetic contributors to obesity.

In a study led by the University of Exeter, researchers have found that individuals with a genetic variant disabling the SMIM1 gene tend to have higher body weight and lower resting energy expenditure. This insight could potentially lead to new approaches for obesity treatment.

The research team is now interested in exploring whether an existing, affordable thyroid medication could effectively treat obesity in individuals lacking both copies of the SMIM1 gene.

The underestimated effect of SMIM1

The SMIM1 gene was discovered just a decade ago during a search for the gene encoding a distinct blood group known as Vel.

This breakthrough came as a result of dedicated efforts to understand the genetic underpinnings of various blood types, leading to the identification of SMIM1 as the gene responsible for the Vel blood group.

Approximately one in 5,000 individuals lack both copies of the SMIM1 gene, rendering them Vel-negative. This genetic rarity has now been linked to a predisposition for higher body weight.

The Exeter study indicates that individuals without both copies of the SMIM1 gene are more likely to be overweight compared to those with at least one functioning copy.

Alongside this, individuals without both copies of the gene exhibit other obesity-associated measures, such as high levels of fat in the blood, signs of fat tissue dysfunction, increased liver enzymes, and diminished levels of thyroid hormones.

Finding new treatments for obesity

For the investigation, the team scrutinized the genetics of close to half a million participants in the UK Biobank cohort. They recognized 104 individuals with the variant leading to the SMIM1 gene’s loss of function.

The team also collaborated with the NIHR National BioResource to obtain fresh blood samples from both Vel-negative and Vel-positive individuals.

Study lead author Mattia Frontini is an associate professor of cell biology at the University of Exeter Medical School.

“Obesity rates have nearly tripled in the past 50 years, and by 2030, more than one billion individuals worldwide are projected to be obese,” said Frontini.

“Obesity is due to an imbalance between energy intake and expenditure, often a complex interplay of lifestyle, environmental, and genetic factors. In a small minority of people, obesity is caused by genetic variants.”

“When this is the case, new treatments can sometimes be found to benefit these people — and we’re now hoping to run a clinical trial to find out whether widely-available drug for thyroid supplementation may be beneficial in treating obesity in people who lack SMIM1.”

Global impact of the genetic variant

Further exploration of these cohorts suggests that the SMIM1 variant could influence obesity in nearly 300,000 people worldwide. This conclusion was reached after analyzing the effects found in four additional cohorts of people with the SMIM1 gene variant.

The experts determined that having the variant had a notable impact on weight, accounting for an average extra 4.6kg in females and 2.4kg in males.

“SMIM1 was only discovered a decade ago, as a long-sought blood group protein on red blood cells, but its other function has remained unknown until now. It’s very exciting to find that it has a more general role in human metabolism,” said study co-author Jill Storry, a professor at Lund University in Sweden.

Modifying the gene to treat obesity

The implications of this study extend beyond mere understanding; they hint at potential therapeutic applications.

Researchers are now exploring whether modifying the SMIM1 gene or its expression could offer new avenues for treating obesity.

Gene therapy and CRISPR technology could potentially be employed to correct the genetic variant responsible for SMIM1 deficiency.

Additionally, lifestyle interventions tailored to individuals with SMIM1 variants might be developed, focusing on specific exercise and dietary recommendations that could mitigate the gene’s effects.

The study provides us with a more in-depth understanding of obesity. As more information on the SMIM1 mechanism is revealed, individuals lacking SMIM1 could receive essential information and support, contributing significantly to the global fight against obesity.

The study is published in the journal Cell Press.

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