Neutrophils help kick off insulin resistance in obesity

By Sally Robertson, B.Sc.Aug 8 2012

Experts have found that neutrophils play an important role in initiating the chronic inflammation that characterizes obesity-induced insulin resistance.

"These results are largely unexpected," said co-author Day Young Oh, from the University of California in San Diego, USA, in a press statement. "Although several immune cells have been established in the etiology of insulin resistance, the role of neutrophils in this process has remained unclear until now."

The team determined the time course of neutrophil infiltration in the adipose tissue of mice fed a high-fat diet (HFD), using fluorescence-activated cell sorting to identify adipose tissue neutrophils (ATNs).

As reported in Nature Medicine, there was a rapid increase in ATN levels after just 3 days of HFD feeding and ATN content remained elevated 12 weeks into the diet. Similarly, the expression of neutrophil elastase, a protease secreted by neutrophils, was significantly increased 3 days into the HFD and remained elevated after 12 weeks.

Consistent with these findings, neutrophil elastase activity was also significantly higher in the HFD mice after 12 weeks than it was in mice fed standard chow.

The researchers then administered a neutrophil elastase inhibitor (at 2 mg per kg of body weight) to a proportion of the HFD-induced obese mice for 14 days and found that these mice had significantly improved glucose tolerance compared with untreated mice.

Based on these findings, the team compared mice carrying a genetic deletion of neutrophil elastase (NEKO mice) with wild-type (WT) mice.

The team reports that after a 10-week HFD, ATN content was approximately 90% lower in the NEKO compared with the WT mice.

The researchers also found that the NEKO mice had markedly higher glucose tolerance and lower fasting insulin concentrations than WT mice, and were substantially more sensitive to insulin.

"Thus, both genetic and pharmacologic loss of function of neutrophil elastase produced improved glucose tolerance with less ATNs, whereas pharmacologic gain of function led to glucose intolerance," writes the team.

Furthermore, a hyperinsulinemic-euglycemic clamp study showed that insulin had a greater ability to inhibit hepatic glucose production and suppress free fatty acid concentrations in the NEKO compared with the WT mice.

"Taken together, these results show that neutrophil elastase deletion leads to a high degree of hepatic and adipose tissue insulin sensitivity," say the researchers.

"We suggest that neutrophils should be considered active participants in the immune-cell-type conversation, which ultimately leads to obesity-induced inflammation and insulin resistance," they conclude.

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