Obesity often leads to severe health problems, but a team of IRP researchers has identified a molecule that might grant an innate resistance to those conditions in some obese individuals.

Hundreds of scientific studies have established that obesity often leads to severe health problems and cuts short many lives. Nevertheless, a significant number of obese people remain healthy despite their excess weight. A new IRP study has now identified a possible molecular marker that distinguishes obese but healthy individuals from those whose weight has negatively affected their health.1

Obesity has long been linked to a set of severe health problems known as metabolic syndrome, which includes type 2 diabetes, cardiovascular disease, and insulin resistance. However, when researchers led by IRP Senior Investigator Charles Rotimi, Ph.D., studied a large group of obese African-Americans, they found that nearly a third of that cohort was ‘metabolically healthy,’ meaning they did not suffer from the metabolic conditions typically associated with obesity.2 Their bodies also had lower levels of inflammatory molecules, an important finding given that inflammation is thought to be the mechanistic link between obesity and metabolic syndrome.3,4

“It’s surprising when you see somebody who is 300 or 400 pounds, but when you look at their blood glucose or blood pressure or lipid profile they are remarkably normal,” says Dr. Rotimi, the new study’s senior author. “It’s not consistent with what we think we should see in people who are obese.”

In an attempt to understand how some of those obese participants avoided inflammation and the metabolic consequences of excess weight, IRP staff scientist Ayo Doumatey, Ph.D., a member of Dr. Rotimi’s lab and the study’s first author, examined the blood of 20 obese women from that group, half of whom were metabolically healthy and half of whom had obesity-related health conditions. Dr. Doumatey specifically measured the levels of 179 microRNAs extremely short DNA-like molecules that regulate how much protein a gene produces by binding to messenger RNA (mRNA) molecules, which help translate genetic instructions into proteins.

“MicroRNAs are associated with cardiovascular disease, and the levels of some of them are also different in obese individuals,” Dr. Doumatey says, “but they have never been investigated specifically in metabolically healthy obese individuals.”

Dr. Doumatey’s analysis identified eight microRNAs present in different concentrations in the metabolically healthy obese participants compared to the unhealthy ones. One of those molecules, known as miR-374a-5p, was also significantly more abundant in the healthy members of a second, independent group of obese men and women. Moreover, in that second group, higher levels of miR-374a-5p were associated with a lower triglyceride-HDL cholesterol ratio, a measure that points to an increased risk of cardiovascular disease when it is elevated.

Dr. Doumatey next consulted a computer database that lists all of the mRNA molecules a specific microRNA can interact with. After filtering her results to include only interactions that had been verified in past experiments and to focus only on mRNAs specifically linked to fat cells, she came up with a list of three mRNA molecules. In yet another sample of obese adults, one of these mRNAs, called CCL2, was present at lower levels in metabolically healthy obese participants compared to those with metabolic abnormalities.

Because CCL2 is a marker of inflammation, Dr. Doumatey theorizes that the higher levels of the microRNA miR-374a-5p she found in her metabolically healthy subjects might lead to lower levels of CCL2 and other inflammatory markers. Lower levels of inflammation, in turn, could protect those individuals from weight-related metabolic problems. She and Dr. Rotimi now plan to test that hypothesis by directly manipulating levels of miR-374a-5p in cultured cells to see the effects on inflammatory markers like CCL2. They will also explore links between miR-374a-5p and a lack of metabolic problems in a more diverse sample of obese individuals, which could allow clinicians to use that microRNA as a screening measure to determine whether someone’s weight is likely to harm his or her metabolic health.

“We are interested in the biology of obesity, and this subset of individuals provides us an opportunity to shed light on how some obese individuals can remain healthy for a long time,” Dr. Rotimi says. “Our findings may also provide a way to understand and perhaps treat the complications of obesity and prevent them in individuals who are metabolically unhealthy.”

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References:

[1] Circulating MiR-374a-5p is a potential modulator of the inflammatory process in obesity. Doumatey AP, He WJ, Gaye A, Lei L, Zhou J, Gibbons GH, Adeyemo A, Rotimi CN. Sci Rep. 2018 May 16;8(1):7680. doi: 10.1038/s41598-018-26065-5.

[2] Paradoxical Hyperadiponectinemia is Associated With the Metabolically Healthy Obese (MHO) Phenotype in African Americans. Doumatey AP, Bentley AR, Zhou J, Huang H, Adeyemo A, Rotimi CN. J Endocrinol Metab. 2012 Apr 1;2(2):51-65.

[3] Inflammation as a link between obesity and metabolic syndrome. Emanuela F, Grazia M, Marco de R, Maria Paola L, Giorgio F, Marco B. J Nutr Metab. 2012;2012:476380. doi: 10.1155/2012/476380.

[4] Proinflammatory and lipid biomarkers mediate metabolically healthy obesity: A proteomics study. Doumatey AP, Zhou J, Zhou M, Prieto D, Rotimi CN, Adeyemo A. Obesity (Silver Spring). 2016 Jun;24(6):1257-65. doi: 10.1002/oby.21482.