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News Excerpt:

Along with a higher risk of heart disease and diabetes, obesity has been linked to a higher susceptibility to colorectal cancer (CRC), among other diseases.

Obesity and its impact on general health:

• Obesity is a chronic disease characterised by the excessive accumulation and storage of fat in the body. 
• Obesity is generally defined by the body mass index (BMI).
• BMI is a number that accounts for the height and weight of the individual. 
• A BMI of 25 kg/m2 or above indicates being ‘overweight’ while 30 kg/m2 indicates ‘obesity’.

Shortcomings of BMI:

• The definition of fat using BMI doesn’t say anything about how fat is distributed in the body. 
• Scientists are interested in this detail because body fat distribution better predicts obesity’s adverse effects.
• The distribution of fat in the body can be described using measures like waist circumference, hip circumference or the ratio between the two, i.e. waist-to-hip ratio.
• But even these estimates don’t indicate whether certain types of body fat distribution put individuals at higher risk of obesity-related diseases.

Not all obese people are at similar risk:

• While it was known that obese individuals have a higher risk of CRC, a Science Advances study published in April 2024 reported evidence that not all obese people are at equal risk.
• Instead, the risk seems to be higher for those who are “generally obese” and those who are “tall and centrally obese”.
• The study argued that different genetic pathways may explain how CRC is caused in different obesity subtypes.
• The study highlights the importance of considering body shape as compared to BMI for risk assessment of CRC.

What is Central obesity?

• Central obesity is an excess accumulation of fat in the abdominal area, particularly due to excess visceral fat. 
• Since visceral fat is supplied by the portal blood system, excess fat in this area can lead to the release of fatty deposits into the bloodstream, causing health-related problems. 

Who is at most risk of Colorectal cancer (CRC)?

• A new study began by analysing the BMI, weight, height, waist circumference, hip circumference, and waist-to-hip ratio of more than 3 lakh people to group them into four body shapes based on their observable characteristics: PC1, PC2, PC3, and PC4.
• PC1 individuals were generally obese.
• PC2 included tall individuals with a low waist-to-hip ratio.
• PC3 included tall individuals with central obesity — with excess fat deposited around the abdomen. 
• PC4 had those who had an athletic body shape.
• PC1 and PC3 individuals were strongly correlated with higher CRC risk while PC2 and PC4 were not associated with CRC risk.
• These associations were also linked to the site at which CRC occurred and the sex of the individual.

Different obesities, different genes:

• A genome-wide association study (GWAS) is used to find correlations between gene variations and traits in large groups of people.
• The research found that a variation in a gene called AKT was implicated in the higher CRC risk for PC1 individuals. 

• • AKT regulates cell survival, insulin signalling, and the formation of blood vessels and tumours in humans.

• Similarly, a variation of the RAF1 gene was found to be implicated in PC3 individuals’ CRC risk. 

• • RAF1 mediates, among other processes, the transformation of normal cells into cancerous cells.
• These genetic variations could explain the increased CRC risk in “generally obese” and “tall and centrally obese” body types.

The genes at play

• Gene expression varies between different body shapes and from tissue to tissue. 
• A tissue is a group of similar cells that perform a specific function. 
• The scientists studied whether the gene variations associated with each body type were expressed distinctly in different tissues.
• The genetic variations associated with risk for PC1 individuals were most highly expressed in the “brain and in the pituitary gland”.
• The pituitary gland is located at the base of the brain and produces hormones important for regulating growth, blood pressure, and functions of the sex organs, the thyroid glands, and the kidneys. 
• In contrast, the variations associated with risk in PC3 individuals were found enriched in “adipose tissue, nerve, cervix uteri, uterus, blood vessel, breast, fallopian tube, and ovary”.

Conclusion of the study:

• The CRC arises in different body shapes through different physiological mechanisms.
• A person’s body shape may change over time and “the study doesn’t provide information on whether and how” these changes “affect their CRC risk.”
• Further, GWAS, the technique the researchers used to identify genes that could be linked to higher CRC risk in PC1 and PC3 individuals, may also identify gene variants that may not be directly relevant to the disease. 
• Recent studies point to cases where obese individuals can be free from cardiac problems, diabetes, and high blood pressure and cholesterol and future studies could examine CRC risk associated with these individuals.