Tiny RNA Molecules Could Explain Different Obesity Characteristics in Prader-Willi Patients, Study Suggests

Differing levels of tiny RNA molecules called micro RNAs (miRNAs) could explain the distinctive features of obesity between patients with Prader-Willi syndrome (PWS) and individuals whose obesity is not related to a genetic disorder, according to a study.

The study, “Differences in circulating microRNA signature in Prader-Willi syndrome and non-syndromic obesity,” appeared in the journal Endocrine Connections.

Hyperphagia, or excessive eating, is a hallmark symptom of PWS and may lead to severe obesity and related complications, including type 2 diabetes, metabolic syndrome, and cardiovascular and respiratory problems. PWS patients have a high prevalence of altered glucose metabolism, particularly obese and adult individuals.

Obesity in PWS patients has distinctive characteristics, such as a higher fat mass percentage in specific body parts as well as reduced fat-free mass compared with people with common obesity. PWS is also characterized by less visceral fat deposits and a predominant accumulation of adipose tissue under the skin. Accordingly, PWS patients have lower insulin levels and higher insulin sensitivity.

miRNAs are tiny RNA molecules that regulate gene expression. They may affect lipid (fat) metabolism, formation of adipose tissue cells called adipocytes, and metabolic activity, among other processes involved in obesity.

Because miRNAs may be released to the blood, they could be a relevant source of information on distinctive molecular alterations in each disorder.

In this pilot study, a research team from Italy aimed to compare circulating miRNAs in PWS to obesity not derived from a genetic disorder, also called essential obesity (OB). For this purpose, they included 10 PWS patients (six women, four men), ages 22-47, with a mean body mass index (BMI) of 37.3 kg/m² (obese), who were compared with 10 sex-matched adults with OB (mean BMI 42.3 kg/m²), ages 24-44. Blood samples were collected from all patients.

Results showed that 34 of the total 362 identified miRNAs had different levels between the two groups. In the OB patients, 13 miRNAs were increased, particularly miR-24-3p, miR-122, and miR-23a-3p, all previously studied in obesity-related disorders for their role in lipid metabolism. And 21 miRNAs were increased in the serum of PWS patients.

Among rarely detected miRNAs in both groups, miR-374a-5p, miR-4701-5p, and miR-1298 were detectable only in patients with OB, while miR-4800-5p and miR-7111-5p were found only in those with PWS.

In individuals with OB, miR-7107-5p was higher in those with steatosis (accumulation of fat in the liver), while 151a-5p, miR-3620-5p and miR-4433-3p were higher in patients without steatosis.

As for patients with PWS, miR-619-5p and miR-4507 were higher in the absence of steatosis, while miR-4656, miR-7847-3p and miR-6782-5p were only detectable in PWS patients with steatosis.

For patients with steatosis, five miRNAs were significantly higher in subjects with OB, while seven miRNAs had increased levels in individuals with PWS.

Conversely, in patients without steatosis, 26 miRNAs were differently expressed in the two groups, 22 of which were higher in people with PWS. However, the liver-specific miR-122-5p was markedly elevated — 50 times higher — in those with OB.

An analysis of the molecular pathways potentially affected by the differential miRNAs levels showed that, in individuals with OB, miR-24-3p, miR-92a-3p, and miR-93-5p were highly associated with cellular lipid metabolism, while higher levels of miR-93-5p were found in pathways involving the insulin receptor and the fibroblast growth factor receptor. In contrast, none of these pathways had elevated miRNA levels in PWS patients.

Overall, different pathway regulation between PWS and OB patients could explain their different adipogenesis — the formation of mature adipocytes — lipid metabolism and storage, and cellular energy expenditure, the team noted.

“Our findings indicate the presence of a distinctive circulating miRNA profile between PWS and OB,” the scientists wrote. “The identification of specific miRNA profile in PWS may represent an additional and valuable [contribution] in the clinical evaluation of hepatic impairment in these patients.”