Effects of obesity and 10 weeks metformin treatment on liver steatosis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in adolescents and adults, and the risk of developing NAFLD increases with obesity. In the present study, it was shown that obesity increased fatty liver (steatosis) using an obese Zucker rat model. Metformin is an oral anti-hyperglycemic agent approved by the FDA for treatment of type 2 diabetes in adults and children >10 years of age. There is insufficient evidence regarding the effects of metformin on pediatric liver steatosis. Thus, in the present study, the effects of 10 weeks metformin treatment on liver steatosis and related serum markers for liver damage was assessed. Lean and obese (n=16 per group) 5-week old female Zucker rats were provided an AIN-93 G diet for 8 weeks to induce NAFLD, and then rats were randomly assigned to 4 groups (8 rats/group): i) lean without metformin (LC), ii) lean + metformin (LM), iii) obese without metformin (OC), and iv) obese + metformin (OM). Rats were provided ad libitum access to the diet containing metformin (1 g metformin per kg of food). Rats were weighed twice weekly and were sacrificed 10 weeks later. Serum was collected to measure the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), leptin and adiponectin. Livers were collected for histological analysis. The results showed that obese rats gained significantly more weight than lean rats in both the control and metformin treatment groups (P<0.001). OM treated rats exhibited a lower degree of liver steatosis compared with the OC rats (P<0.04). There were no significant differences in serum ALT levels between the groups. However, obesity significantly increased serum AST levels in both the control and metformin treatment groups (P=0.01). The ratio of leptin to adiponectin was increased in obese compared with the lean rats in both the control and metformin treatment groups (P<0.0001). There was no effect of metformin on serum biomarkers. In summary, short-term metformin treatment decreased liver steatosis but did not affect the serum markers of liver steatosis.

Short-Term Metformin Treatment Enriches Bacteroides dorei in an Obese Liver Steatosis Zucker Rat Model

“…Although these rats have gained more weight compared to obese casein-fed rats, they had lower liver steatosis and contained lower blood serum levels aspartate aminotransferase AST, alanine aminotransferase ( Hakkak et al, 2018 ). Similar results were observed for obese Zucker rats fed an AIN-93 G diet during metformin treatment ( Hakkak et al, 2021 ). Prior research within murine models and human subjects has shown that short-term metformin treatment was sufficient to reduce liver steatosis ( Lin et al, 2000 ; Madsen et al, 2015 ; Wang et al, 2016 ; Hakkak et al, 2021 ).…”

“…Similar results were observed for obese Zucker rats fed an AIN-93 G diet during metformin treatment ( Hakkak et al, 2021 ). Prior research within murine models and human subjects has shown that short-term metformin treatment was sufficient to reduce liver steatosis ( Lin et al, 2000 ; Madsen et al, 2015 ; Wang et al, 2016 ; Hakkak et al, 2021 ).…”

“…Non-alcoholic fatty liver disease is the leading cause of liver disease in adolescents in the United States and world, and the risk has increased with the rise of obesity ( Lazo et al, 2013 ; Welsh et al, 2013 ). Data from our animal studies using the obese Zucker ( fa/fa ) rat model reported that obesity increases fatty liver (steatosis) and that obese Zucker rats can develop fatty liver by the starting age of 8 weeks ( Hakkak et al, 2018 , 2021 ).…”

“…In addition, metformin appears to improve lipid profiles in obese children ( Kay et al, 2001 ; Atabek and Pirgon, 2008 ). Furthermore, metformin is not only used for the treatment of diabetes, but also for various other diseases including cancer, cardiovascular diseases, and liver steatosis ( Lin et al, 2000 ; Foretz et al, 2014 ; Madsen et al, 2015 ; Wang et al, 2016 ; Fujita and Inagaki, 2017 ; Lv and Guo, 2020 ; Hakkak et al, 2021 ).…”

“…We have previously shown that short-term (10 weeks) metformin treatment is a useful model for early adolescent obesity related diseases, using obese Zucker rat model ( Hakkak et al, 2021 ). In this model, we were able to show that this short-term metformin treatment can protect against NAFLD.…”