Gene Study Challenges Idea of Healthy Obesity

A genetic analysis of abdominal fat from obese individuals added further evidence against the idea of metabolically healthy obesity, Swedish scientists said.

In response to insulin stimulation, the fat from obese individuals who were insulin sensitive, which is considered an indicator of metabolically healthy obesity, showed similar gene expression patterns to the fat from insulin-resistant obese individuals, said Mikael Rydén, PhD, of the Karolinska Institute in Stockholm, and colleagues.

The gene expression patterns in insulin-sensitive and insulin-resistant obese individuals differed markedly from that of non-obese controls, they wrote in Cell Reports.

The abnormal gene expression patterns in obese individuals were not influenced by cardiovascular or metabolic risk factors including gender, waist-to-hip ratio, heart rate, blood pressure, or fasting lipid or insulin levels, they added.

"Our study suggests that the notion of metabolically healthy obesity may be more complicated than previously thought, at least in subcutaneous adipose tissue," Rydén said in a statement. "There doesn't appear to be a clear transcriptomic fingerprint that differentiates obese subjects with high or low insulin sensitivity, indicating that obesity per se is the major driver explaining the changes in gene expression."

"Insulin-sensitive obese individuals may not be as metabolically healthy as previously believed," Rydén added. "Therefore, more vigorous interventions may be necessary in these individuals to prevent cardiovascular and metabolic complications."

The study included 50 obese patients enrolled in a clinical trial examining the outcomes of gastric bypass surgery. Participants were in their 40s, and their mean body-mass index was 39 kg/m2. The study also included a control group of 15 healthy non-obese individuals.

The investigators biopsied subcutaneous abdominal white fat tissue from participants before and 2 hours into a hyperinsulinemic euglycemic clamp procedure. "We chose this short period of hyperinsulinemia in order to evaluate direct transcriptional effects of insulin, assuming that longer duration of stimulation may cause secondary effects on gene transcription," Rydén's group said.

Based on the glucose uptake rate during the clamp procedure, the investigators identified 21 obese participants as insulin sensitive and 29 as insulin resistant. Insulin sensitivity was considered an indicator of metabolically healthy obese individuals.

The investigators analyzed the biopsy samples using global transcriptional profiling with the 5'cap analysis of gene expression (CAGE). In response to insulin stimulation, the expression of 231 genes was altered in the obese patients. Nearly half of these genes (108) were altered in both the insulin-sensitive and insulin-resistant obese individuals. In contrast, only four genes were altered in response to insulin in the non-obese group.

The genes in question were involved in insulin signaling, metabolic function, mitogen-activated protein kinase (MAPK) signaling, circadian rhythm, and cancer, the investigators said.

"There are some caveats with the present study," the authors noted "Because the obese subjects were scheduled to undergo bariatric surgery, our results may only pertain to individuals with severe obesity."

In addition, the study only analyzed subcutaneous abdominal white fat tissue, and gene expression in response to insulin might be different on other types of fat tissue, such as skeletal muscle and liver fat, they said.

Nevertheless, "this study demonstrates that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity," they concluded.

"The findings suggest that vigorous health interventions may be necessary for all obese individuals, even those previously considered to be metabolically healthy," Rydén said. "Since obesity is the major driver altering gene expression in fat tissue, we should continue to focus on preventing obesity."

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