Not all fat is equal: Body fat distribution linked to cancer risk

The global rise in obesity is staggering. Obesity has doubled in over 70 nations within a span of a mere four decades. By the year 2035, experts predict four billion individuals will be affected by it.

Next to diabetes and heart disease, obesity is closely linked with cancer, the world's number-two leading cause of death. But a new study indicates that a much simpler narrative governs cancer risk at a deeper level: the location of the stored fat.

Body fat or adipose tissue serves a purpose beyond energy stored. It works as a hormone-releasing organ and has a role in inflammation and metabolism and other long-term health determinants. But all fat doesn't behave similarly. Visceral fat deposited deep inside organs releases molecules that are linked with tumor growth and inflammation.

Subcutaneous tissue of the skin also produces estrogen that can nourish certain cancers of men and postmenopausal women.

Fat at the hips and thighs, or what we refer as gluteofemoral fat, seems to play a very different, perhaps less toxic function. Even stored fat in organs such as the pancreas and the liver may propel disease as we are just starting to grasp.

That diversity has posed a significant question: Does the pattern of distribution of fat throughout the body shed any light upon why individuals are more susceptible to cancer or less susceptible as opposed to others regardless of their body mass index or BMI being identical?

BMI has traditionally been the usual measure of obesity because it's simple to compute from height and weight. But BMI won't indicate if and how much fat is compactly stored around organs or resides primarily under the skin. Two individuals can have the same BMI with distinctly different health effects based on the distribution of their fat.

Heart researchers have long pushed for a wider definition of obesity because they've noted that visceral fat individually increases the risk of diabetes and heart disease.

When the European Association for the Study of Obesity last updated guidelines, it said BMI as a single measure was too crude a tool with which to measure health risk. How fat distribution affects cancer has long stayed much less clear.

In order to examine that relationship, researchers at the University of Bristol and globally turned to Mendelian randomization, a method that utilizes genetic variation as natural experiments. because genetic material is randomly distributed at the time of conception, this tactic can restrict the bias and confounding that blur observational studies.

The researchers looked at how five individual fat traits—subcutaneous abdominal, visceral, gluteofemoral, liver, and pancreatic fat—and BMI affected the risk of 12 cancers that have been associated with obesity. These were breast, ovarian, colorectal, pancreatic, endometrial, liver, kidney, thyroid, gallbladder, multiple myeloma, meningioma, and esophageal adenocarcinoma.

Data were from the UK Biobank research that recruited more than half a million adults from 2006 through 2010. Nearly 39,000 of those actually had their fat reserves measured with their MRI scans and were analyzed with deep learning software. Supplemental cancer data were from both the UK Biobank and the FinnGen study as an extra measure of robustness.

They also studied 24 of the molecule's characteristics—hormones, proteins that are linked with inflammation, and regulators of the metabolism—that may elucidate why fatty tissue produces cancer.

The results revealed dramatic contrasts. Visceral fat was the top risk. It was also considerably tied with high risks of endometrial, ovarian, and colorectal cancers. Links were weaker with subcutaneous fat, yet it still played a part in hormone-regulated cancers such as breast cancer.

Fat in the hips and thighs sometimes appeared neutral or even protective, a reminder that not every type of fat is equally harmful. Meanwhile, liver and pancreatic fat showed troubling connections to certain cancers, hinting at a role for fat stored within organs themselves.

"These findings back the mounting consensus that BMI, while informative at a population level, may be too rough a tool with which to estimate individual health risks of cancer," concluded lead author of the research Dr. Emma Hazelwood, who has just finished a PhD at Bristol. "What our research suggests is that there isn't one size that fits all with cancer and thus a more individualized approach to cancer prevention among obese individuals may be ideal."

The research not only went as far as correlating cancer with stored fat. It also demonstrated that stored fat differing from one another influences hormones and proteins already established as tumor growth promoters.

Visceral fat around organs, for example, elevated inflammation markers, while other depot modified insulin signalling and fatty acid processing. Visceral fat also impacted sex hormones like testosterone and sex hormone-binding globulin levels that govern the action of hormones in the body.

By tracing out such chemical changes, researchers found evidence supporting that the effect of fat distribution as a cancer determinant may be mediated partly through such molecular pathways. It suggests reducing harmful fat depots or controlling the hormonal and inflammatory changes they bring may help lower the risk of cancer.

The study, published in the Journal of the National Cancer Institute, was among the first to apply genetic methods to distribution of fat and cancer. Its application of MRI scans to measure accurately and then integrate with wide-ranging genetic data provided a powerful insight of the issue. But the authors also highlighted some shortcomings.

UK Biobank participants were generally healthier than the average population and may consequently underestimate risks. Certain cancers were fairly rare and limit the ability of conclusions of that sort. And while Mendelian randomization can suggest directionality of causation, it also has a number of genetic assumptions underlying it that are not quite correct.

Despite those reservations, the research lends backing to recent calls that measures of obesity must be revised. "Our evidence-based Cancer Prevention Recommendations highlight the value of a healthy weight as a means of reducing cancer risk," said World Cancer Research Fund Head of Research Funding Dr. Julia Panina. "While this remains a cornerstone of principle, mounting scientific evidence reveals that body composition—and, in particular, distribution of fat around the body—also possesses a crucial key."

It was jointly funded with World Cancer Research Fund and Cancer Research UK as part of the Integrative Cancer Epidemiology Programme. It was conducted at the Integrative Epidemiology Unit of the Medical Research Council at Bristol University.

This research puts a spotlight on the necessity of going beyond BMI both in research and medical practice. Physicians one day may use imaging technologies or genetic tests to determine individuals at ultimate risk according to where their body stores their fat as opposed to how much they weigh.

Future treatments could aim at reducing shrinking visceral or organ fat or reducing the inflammatory and hormonal changes these depots cause. Tailored techniques of this sort could forestall additional cancers and guide therapy.

As worldwide incidence of obesity increases, this more refined understanding of the role of fat could yet prove important in reducing cancer's global toll.

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