Is it noise or size? That's a key question for researchers looking to understand how fat tissue affects health. In a new publication, Mayo Clinic researchers are tipping the scales toward size after finding that in most forms of human obesity, the size of the fat cells, not inflammation, is the deciding factor on how the cells manage insulin.

Obesity is defined by excess fat (adipose) tissue and is often linked to chronic inflammation. Research on fat tissue donated by people with obesity tends to show higher levels of inflammation as measured by inflammatory cells, such as macrophages, and inflammatory signals, such as cytokines. One way obesity is hypothesized to contribute to chronic disease is by creating a background "noise" of inflammation. That noise, it is thought, could prevent the body from responding efficiently to other sources of inflammation (tissue damage, infection, cancer). Over time, that slow response leads to an accumulation of damage and chronic illness.

But researchers know that the bigger a fat cell gets, the worse it's able to do its job, which is to safely hold onto fat when directed to do so by insulin. And in the case of insulin resistance or inflammation, it still isn't clear which comes first.

Fat Cell Size in Human Obesity

In 2015, Michael Jensen, M.D., a Mayo Clinic endocrinologist, began studying inflammation in fat tissue.

"At that time, inflammation in adipose tissue was a hot topic, but no one had studied it in humans in such a way as to confirm whether the animal data was applicable to humans," Dr. Jensen says. "Because my lab had the unique capacity to do so, we designed and conducted the studies to test whether accepted measures of inflammation can predict adipose tissue insulin resistance."

Their results were recently published in the journal Diabetes. The team found that fat cell size was tightly linked to adipose tissue insulin resistance, but markers of inflammation were not. These findings were a surprise to the team.

Dr. Jensen's lab studies the effects of obesity and how fat tissue and fat distribution influence health. Clockwise from top left: Kelli Lytle, Ph.D.; Michael Jensen, M.D., the Thomas J. Watson Professor in Honor of Dr. Robert Frye; and Paola Ramos, Ph.D.

Obesity Therapies: New Direction?

"I was 'all in' on the inflammation hypothesis, so the whole thing was a surprise," says Dr. Jensen. "In fact, when we started getting hints that inflammation wasn't the cause in our first study, we modified another study so we could test that hypothesis in a second cohort."

The publication reports on 86 participants with normal weight or obesity at baseline and included a subgroup of 25 volunteers with obesity before and after weight loss. The authors tested if markers of fat tissue inflammation (macrophage content, cytokine gene expression and senescent cell burden) predicted fat tissue insulin resistance. They found that the relationship between those markers and fat tissue insulin resistance was not statistically significant, but there was a strong relationship between insulin resistance and fat cell size in cells from the abdominal area. In the participants who lost weight, 10% weight loss reduced fat cell insulin resistance, but did not affect inflammatory markers.

"This means that therapies targeting adipose inflammation likely won't help with insulin resistance," says Dr. Jensen.

To find what will, the team plans to continue this work by measuring the fat cell proteins involved in insulin action and designing further studies.

In addition to Dr. Jensen, the authors are Ana Elena Espinosa De Ycaza, M.D., Esben Søndergaard, M.D., Ph.D., Maria Morgan-Bathke, Kelli Lytle, Ph.D., Danae Delivanis, M.D., Paola Ramos, Ph.D., and Barbara Gisella Carranza Leon, M.D. This work was supported by federal grants from the National Institutes of Health. The authors report no conflict of interest. To read the complete paper, see the journal.

— Sara Tiner, May 17, 2022