Mitigation of MAFLD in High Fat-High Sucrose-Fructose Fed Mice by a Combination of Genistein Consumption and Exercise Training

Abstract

Purpose

Metabolic dysfunction-associated fatty liver disease (MAFLD) is fueled by escalations in both sedentary behavior and caloric intake and is noted in obese type 2 diabetic (T2DM) patients. This study aimed to examine the effects of exercise and the phytoestrogen genistein in mice fed a high fat (60% fat) high sugar (55% fructose with 45% sucrose), HFHS diet.

Methods

Male C57BL/6J mice were assigned to five groups: HFHS, HFHS with genistein (600 mg/kg diet, HFHS+Gen), HFHS with moderate exercise (HFHS+Ex), and HFHS with combined genistein and moderate exercise (HFHS-Gen+Ex). Control lean mice were fed standard chow and water. Exercise consisted of 30-minute sessions of treadmill running five days/week for the 12-week study duration. Body weight was assessed weekly. Liver, kidney, fecal pellets and serum were extracted at the end of the study and maintained at −80°C.

Results

After 12 weeks of treatment, mice in the HFHS group had the highest hepatic lipid content. Plasma levels of glucose, insulin, leptin, cholesterol, amylin, and total fat content were significantly elevated in HFHS mice compared to control mice. HFHS feeding increased protein expression of carnitine palmitoyltransferase 1b (CPT-1b isoform) in gastrocnemius, CPT1a, glucose transporter protein 2 (GLUT2), glucocorticoid receptor (GR), and fructose 1,6-bisphosphate 1 (FBP1) expression in liver. Exercise alone had minor effects on these metabolic abnormalities. Genistein alone resulted in improvements in body weight, fat content, amylin, insulin sensitivity, and liver histopathology, GR, FBP1, and acetyl-CoA carboxylase 1 (ACC1). Combination treatment resulted in additional metabolic improvements, including reductions in hepatic lipid content and lipid area, alanine transferase activity, CPT1b, and CPT1a.

Conclusion

Our results indicate that a HFHS diet is obesogenic, inducing metabolic perturbations consistent with T2DM and MAFLD. Genistein alone and genistein combined with moderate intensity exercise were effective in reducing MAFLD and the aberrations induced by chronic HFHS feeding.

Keywords:

• Soy isoflavone
• genistein
• exercise
• western diet
• diabetes
• hepatic steatosis

Abbreviations

ACC, acetyl CoA carboxylase; ALT, alanine transferase; AUC, area under the curve; CMCVD, common markers of cardiovascular disease; CPT, carnitine palmitoyltransferase; Ex, exercise training; FAS, fatty acid synthase; FBP, fructose-1,6-bisphosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Gen, genistein; GLUT, glucose transporter protein; GR, glucocorticoid receptor; GTT, glucose tolerance test; HFHF, high fat high fructose; HFHS, high fat high sugar; MAFLD, metabolic dysfunction-associated liver disease; NAFDL, nonalcoholic associated liver disease; NASH, nonalcoholic steatohepatitis; SREBP-1, sterol regulator element binding protein 1; T2DM, type 2 diabetes mellitus.

Acknowledgments

Amy Fisher and Chaheyla St Aubin were supported through the Biomedical Sciences Program, College of Graduate Studies. This work was supported by Midwestern University Intramural funds (TLB, L.A.), Diabetes Action and Research Education Foundation (L.A.) and the Midwestern Arizona Alzheimer’s Consortium (TLB, L.A.). We thank Mr. Tatum Banayat for helpful technical assistance.

Disclosure

The authors report no conflicts of interest in this work.