Endocrine Abstracts

Background: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in obese individuals. GLP-1 agonists, such as semaglutide, and SGLT-2 inhibitors, such as empagliflozin, are well known to be beneficial in NAFLD, while other incretins, like peptide tyrosine tyrosine 3-36 (PYY3-36), might be also useful for the treatment of NAFLD. We directly compared the effects of semaglutide alone and in combination with peptide tyrosine tyrosine 3-36 (PYY3-36), empagliflozin and semaglutide+empagliflozin as well as antagonists of GLP-1 and PYY on liver health.

Methods: High-fat diet (HFD)-induced obese male Wistar rats (n=55; mean weight 262 g) were randomized into the following treatment groups: semaglutide, semaglutide+PYY3-36, empagliflozin, semaglutide+empagliflozin, JNJ-31020028 (NPY-Y2 receptor antagonist), JNJ-31020028+exendin 9-39 (GLP-1 antagonist), and saline. Animals had free access to high- and low-fat diet. Body weight and food preference were measured on a daily basis. After an observation period of 8 weeks, liver samples were histologically evaluated (modified Kleiner steatosis score for rodents, higher scores indicating higher grades of steatosis).

Results: Semaglutide and more pronounced semaglutide+PYY3-36 treatment led to weight loss, reduced overall food intake and (less pronounced) reduced high-fat preference compared to saline controls. Although less effective regarding food intake/body weight, semaglutide monotherapy revealed similar beneficial effects on the liver as semaglutide+PYY3-36, which had both antisteatotic effects (mean score 0.7±1.2 for semaglutide alone and 0.2±0.5 for the combination). Empaglifolzin had no effects on body weight and food preference, but was effective in reducing steatosis alone (mean score 0.8±0.8) and more pronounced in combination with semaglutide (mean score 0.0±0.0). JNJ-31020028, an antagonist of the NPY-Y2 receptor, and the combination of JNJ-31020028 and exendin 9-39 led to an increased high-fat diet preference and to the worsening of steatosis compared to saline treatment (mean score 2.3±0.6 in both groups).

Conclusions: Semaglutide, semaglutide+PYY3-36 combination therapy, empagliflozin, and semaglutide+empagliflozin are highly effective in improving liver health. Interestingly, treatment with GLP-1 and PYY (NPY-Y2-R) antagonists led to the aggravation of hepatic steatosis. This underlines the potential of GLP-1 and PYY-36 agonists in the treatment of obesity and related NAFLD. The positive effects of empagliflozin on liver health, however, seem to be independent of body weight and food preference. Further approaches will go for underlying mechanistical aspects.