Study Shows Mechanism of Empagliflozin's Effects on Obesity, Insulin Resistance

Four years after the landmark finding that empagliflozin could reduce the risk of cardiovascular death in patients with type 2 diabetes (T2D), the sodium glucose cotransporter 2 (SGLT2) inhibitor and others in the class are on their way to becoming all-purpose weapons for a variety of cardiometabolic ills, from heart failure to renal decline.

But as the original studies for empagliflozin showed, the drug allows patients to lose modest amounts of weight—and desirable effect for those with T2D. Now, a group of researchers from Japan report on experiments with mice that detail just how the drug slows the progression of obesity and insulin resistance, by promoting energy expenditure and reducing inflammation.

The findings have important implications, as the study confirms “the potential clinical utility of empagliflozin for the treatment of obesity and related metabolic disorders, such as insulin resistance, type 2 diabetes, and NASH,” or nonalcoholic steatohepatitis. Prevalence of NASH is increasing alongside obesity, and earlier studies have pointed to empagliflozin as the first choice in treatment.

Led by senior author Tsuguhito Ota, MD, PhD, of Asahikawa Medical University, the team had previously reported that empagliflozin could prevent weight gain, insulin resistance, and inflammation in lean mice who were fed a high-fat diet. In the team's new paper in BMJ Open Diabetes Research & Care, it explores whether the drug can exert the same effects on mice already affected by obesity and insulin resistance, “due to almost complete lack of uncoupling protein 1 expression in white adipose tissue,” along with inflammation in the tissue and the liver.

Researchers seeking treatment for obesity have sought ways to deliver uncoupling protein 1 to cells, either by gene transfer or other methods, as cells lacking this protein are unable to shed excess fat stores. Also called thermogenin, is it best-known for helping babies generate heat to prevent shivering when their body weight is still low.

Ota’s team fed mice a high-fat diet for 8 weeks, after which they exhibited obesity, low-grade insulin resistance, and chronic inflammation. A control group was fed a normal diet. Then, half the mice on the high-fat diet were then treated with empagliflozin for 8 weeks, which boosted their excretion of glucose through the urine—the known glucose-lowering mechanism of action for SGLT2 inhibitors. After another 3 weeks, the researchers took a series of measurements on energy expenditure, respiratory exchange ratio, and oxygen and cardon dioxide production.

They report that treatment with empagliflozin suppressed weight gain, insulin resistance, and hepatic steatosis. “Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to energy level expenditure,” the team wrote.

The paper reported the following effects in mice treated with empagliflozin:

• Compared with the high-fat diet group, the treated group decreased lipid accumulation, meaning the drug not only prevented weight gain but also reversed it by enhancing energy expenditure and heat generation.
• SGLT2 inhibition promoted fat browning by increasing the level of uncoupling protein 1; the researchers reported enhanced expression of genes that facilitate this process. Brown fat is considered healthy fat compared with white fat. When activated, brown fat burns white fat; stimulating it has long been seen as a way to promote weight loss.
• Empagliflozin decreased expression of cytokines that promote inflammation, while promoting anti-inflammatory markers.
• Scientists were able to study adipose tissue macrophages and calculate that their rate dropped in mice on the high-fat diet once they were treated with empagliflozin.
• Experiments showed that the mice on the high-fat diet treated with the drug still had more liver macrophages than the mice fed a normal diet, but that treatment with empagliflozin reduced inflammation in the liver by causing a shift to an anti-inflammatory macrophage known as M2.

Overall, the researchers found that use of empagliflozin stopped obesity from progressing, while “reducing oxidative stress, inflammation, and insulin resistance,” through a dual mechanism: reducing overall macrophage accumulation, while activating anti-inflammatory macrophages in white fat and in the liver. This reversed pancreatic B-cell dysfunction, alleviating glucose intolerance and insulin resistance.

Empagliflozin, the authors concluded, “may be the therapeutic option for obesity, insulin resistance or non-alcoholic fatty liver disease by calorie loss and through enhanced energy expenditure and alternative macrophage activation.”

Reference

Xu L, Nagata N, Chen G, et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diab Res Care. 2019;7:e000783. doi:10.1136/bmjdrc-2019-000783.