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First-ever research connects obesity to age and gender

[Sept. 5, 2023: Staff Writer, The Brighter Side of News]

It's reasonable to speculate that factors like hormones and physiological differences could be pivotal contributors to disease risks. (CREDIT: Creative Commons)

With obesity becoming an increasingly pressing global health concern, scientists continue their relentless search for its causes. Historically, the narrative has placed emphasis on a myriad of genes and environmental factors that determine weight and body size. However, recent groundbreaking research has added to the growing list of factors, illustrating the nuanced roles of sex, age, and specific genes in determining one's obesity risk.

In a study published in the journal Cell Genomics, a team of researchers highlighted new biological pathways potentially underlying obesity. They emphasized the often-overlooked influence of sex and age on health and disease trajectories.


A Multifaceted Disease Mechanism

John Perry (@jrbperry), a renowned geneticist and professor at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, U.K., and the senior author of the study, commented on the findings. “There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone,” Perry remarked.

While it's unrealistic to assume vastly distinct biologies among different individuals, it's reasonable to speculate that factors like hormones and physiological differences could be pivotal contributors to disease risks.


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Deciphering the Role of Sex in Obesity

To gain insights into the contribution of sex to obesity risk, Perry's research team dived deep into the genetic makeup of 414,032 adults from the comprehensive UK Biobank study. They meticulously sequenced the exome – the segment of the genome responsible for coding proteins. Their aim? To uncover gene variants associated with body mass index (BMI) differences in men and women. BMI, calculated from an individual’s height and weight, serves as a proxy for obesity.

Their pursuit was not in vain. They identified five genes linked with BMI in women and two in men. Of these, three genes, namely DIDO1, PTPRG, and SLC12A5, were found to be associated with a significantly higher BMI in women. These genes appeared to have negligible effects on men. A startling 80% of women with variants in DIDO1 and SLC12A5 were categorized as obese based on their BMI.


Moreover, individuals with the DIDO1 variant were also found to have an association with higher testosterone levels and an increased waist-to-hip ratio – both established markers for obesity-related complications such as diabetes and cardiovascular diseases. The SLC12A5 variant, on the other hand, was linked with a greater likelihood of type 2 diabetes.

The discovery of these gene variants underscores the complexity of obesity's genetic landscape. More importantly, it unveils genes that play critical roles in obesity among women, yet remain inconsequential for men.


Age as a Crucial Player

Not content with their findings, the team further investigated age-specific genetic influences. They focused on gene variants that influenced body size during childhood, using participant recollections as a data source.

Graphical Abstract: These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity. (CREDIT: ScienceDirect)

Here, two genes, OBSCN and MADD, emerged as potential influencers. While those with OBSCN variants were more likely to have been heavier during childhood, the opposite was true for carriers of the MADD variant. Interestingly, the genetic influence of MADD did not carry over into adulthood, pointing to age-specific effects on body size.


Perry, reflecting on their discoveries, voiced his surprise, “What’s quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death.” Given that obesity has been traditionally understood as a brain-related disorder influenced by biological and environmental factors, these new findings were unexpected. “There’s currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity.”

Distributions of adult BMI by sex. (A) In all UK Biobank participants; (B) among carriers of rare variants (DMG, damaging; PTV, protein truncating) in genes associated with sex-stratified BMI. Mean and 95% CI for each group are indicated by horizontal bars and boxes. (CREDIT: ScienceDirect)

Looking Ahead

Eager to expand on their groundbreaking revelations, the team is now setting their sights on a more extensive and diverse population study. They also aim to study these genes in animal models, hoping to glean deeper insights into their functional dynamics and links with obesity.


“We’re at the very earliest stages of identifying interesting biology,” Perry shared. He remains hopeful about the implications of their work. “We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity.”

For more science news stories check out our New Discoveries section at The Brighter Side of News.


Note: Materials provided above by the The Brighter Side of News. Content may be edited for style and length.


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