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February 12, 2021

Body fat investigation provides insights for ‘obesity paradox’

By Elizabeth Zimmermann

The Obesity Paradox

Excerpted from a 2009 Mayo Clinic Proceedings article, The Obesity Paradox: Perception vs Knowledge.

"Data from several epidemiological studies, including the Framingham Heart Study, have found a positive relationship between obesity and mortality, in particular cardiovascular mortality. However, several cross-sectional, retrospective database studies … have found an inverse correlation between body mass index (BMI) and mortality, often termed the obesity paradox."

You are what you eat.

A common phrase, but one that Mayo Clinic researchers have recently documented in a new study published in Science Advances.

"It appears that the food we eat may modulate the severity of inflammation, organ failure and even death," says Vijay Singh, M.B.B.S., M.D., a gastroenterologist and molecular biology researcher at Mayo Clinic, and senior author of the study. "In our research, we found that when a person is stricken by acute pancreatitis their stored body fat rapidly breaks down in a way that can be deleterious if its composition is more unsaturated. Unsaturation of a fat results from the double bonds in its chemical composition.”

The researchers believe that what is referred to as the obesity paradox, or a perceived higher body mass index (BMI) threshold for severe acute pancreatitis in some patients, may be explained by composition of a person's visceral fat accumulated before the disease. The rapid breakdown of this fat and the action of the released unsaturated or essential fatty acids during acute illness worsen the disease course. Their findings may also hold true for other serious conditions with sudden and rapid progression in which the 'obesity paradox' is described, he says.

In the article, Dr. Singh and his colleagues describe their findings, observed using four different methods: meta-analysis, mice models, cellular responses and chemical assays.

Gathering existing evidence

artistic rendering of male torso with measuring tape, and side view cut away of abdomen showing visceral and subcutaneous fat

The human body contains two types of fat, or adipose tissue. Subcutaneous adipose tissue is what contributes to broadened waistlines, hips and thighs. Visceral adipose tissue is deep in the body, mainly the belly, cushioning and insulating the organs. Both of these contribute to the BMI of a person.

In the meta-analysis, or review of existing, relevant scientific studies, the researchers examined the effect of obesity on the severity of acute pancreatitis. Additionally, they filtered the data in the context of dietary patterns of the countries in which the studies were conducted.

They found that in places where diets are typically low in saturated fats – worse outcomes for people with acute pancreatitis were noted in leaner populations or patients with lower BMIs, compared to countries such as the U.S., where the average diet includes much more saturated fat and the population tends to have a higher BMI.

Butter versus oil, a little chemistry lesson

Saturated fats like butter are typically solid at room temperature. Unsaturated fats are those that are liquid, such as olive or corn oil. In the human body, fat is stored as triglycerides, which can have different compositions based on consumed dietary fat. Triglycerides are comprised of saturated or unsaturated fatty acids in various combinations. Normally, without disease, these different fats are slowly broken down as needed, to make different products for activities like supplying energy, making hormones, cell-to-cell communication, or keeping cells structurally healthy.

artistic rendering of the topic of the paper, including geographic, dietary, physiological and biochemical references
In the paper, Dr. Singh and his colleagues thoroughly describe the processes depicted here. NEFA - non-esterified fatty acids; PNLIP - pancreatic triacylglycerol lipase precursor; TG - triglyceride.

Linoleic acid – the investigators note – is an 'essential fatty acid,' a substance that warm blooded animals, including humans, need in small amounts but cannot make on their own. Essential fatty acids have more than two double bonds and typically come from cold sources of dietary fat (e.g. fish or cooking oils).

Linoleic acid consumption has increased substantially since the 1950s, says Dr. Singh. With that, the fat stores in the body, which are attacked during pancreatitis, have become enriched in linoleic acid. He also cites previous research showing the level of linoleic acid in fat stores to average about 25% in patients with severe pancreatitis, which is more than twice what used to be the norm in the U.S.

Although essential, rapid breakdown and release of excess stored unsaturated fatty acids like linoleic acid into the body can interfere with the normal healthy processes vital for survival in humans (or mice). Dr. Singh explains that when this occurs in severe acute pancreatitis, it affects the body's immune system, ramping up inflammation, and potentially could lead to severe infection, organ failure or death.

Learning from the models

artist's rendition of the chemical and molecular processes
Role of the exocrine pancreas in systemic injury during acute pancreatitis.

After analyzing the human studies, Dr. Singh and his colleagues tested both the idea that the dietary fat affects body fat composition, and whether original composition of visceral fat affects outcomes in severe acute pancreatitis. Using mouse models, they found that the type of dietary fat (~70% saturated or unsaturated between two groups) led to changes in visceral triglyceride composition, increasing the percentage of saturated or unsaturated body fats accordingly. When acute pancreatitis was initiated, lean models with high unsaturated fat intake had worse outcomes than the obese models with high saturated fat intake.

Dr. Singh explains that stored unsaturated fat – or what he calls 'oily fat' – is broken very rapidly into fatty acids, whereas saturated, or 'buttery fat', is slow to break down. The unsaturated fatty acids are also more stable in the blood, so the effect is multiplied. The result? Excess unsaturated fatty acids, which are more cytotoxic than their saturated counterparts, and during an acute illness, can be deadly.

This process of breaking down visceral fat into fatty acids is called lipolysis. And linoleic acid led more readily to that breakdown than the saturated fat used in the study diet (palmitic acid).

"Because by nature unsaturated or essential fatty acids are more water stable at warm temperatures, they are able to more freely accumulate and spread through the body, causing damage to individual cells and whole organ systems," says Dr. Singh. "We believe that could contribute to cytokine storms and organ failure in previously healthy people."

"In an apparent paradox, we found that saturated fatty acids interfered with this lipolysis, and when released were unstable on their own. This caused less cell injury," says Dr. Singh. "When we introduced saturated dietary fats, despite the mice weighing more, and having more (saturated) fat; these mice had reduced breakdown of visceral fat into the fatty acids that led to worse outcomes."

Dr. Singh and his colleagues now want to study the mechanisms by which the unsaturated fatty acids damage mitochondria, along with finding ways to prevent the rapid breakdown of the stored fat in acute diseases. Mitochondria generate energy to power individual cell function. The researchers believe that at the most basic level, protecting the mitochondria from fatty acid induced injury will lead to less cell death, inflammation and subsequent organ failure.

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Tags: animal model, basic science, biomedical research, discovery research, Findings, gastroenterology, molecular biology, News, obesity, pancreatitis, Progress Updates, Vijay Singh

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