title: A return to ad libitum feeding following caloric restriction promotes hepatic steatosis in hyperphagic OLETF rats.
abstract: Hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats develop obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD), but lifestyle modifications, such as caloric restriction (CR), can prevent these conditions. We sought to determine if prior CR had protective effects on metabolic health and NAFLD development following a 4-wk return to ad libitum (AL) feeding. Four-week-old male OLETF rats (n = 8-10/group) were fed AL for 16 wk (O-AL), CR for 16 wk (O-CR; ∼70% kcal of O-AL), or CR for 12 wk followed by 4 wk of AL feeding (O-AL4wk). CR-induced benefit in prevention of NAFLD, including reduced hepatic steatosis, inflammation, and markers of Kupffer cell activation/number, was largely lost in AL4wk rats. These findings occurred in conjunction with a partial loss of CR-induced beneficial effects on obesity and serum triglycerides in O-AL4wk rats, but in the absence of changes in serum glucose or insulin. CR-induced increases in hepatic mitochondrial respiration remained significantly elevated (P < 0.01) in O-AL4wk compared with O-AL rats, while mitochondrial [1-(14)C]palmitate oxidation, citrate synthase activity, and β-hydroxyacyl-CoA dehydrogenase activity did not differ among OLETF groups. NAFLD development in O-AL4wk rats was accompanied by increases in the protein content of the de novo lipogenesis markers fatty acid synthase and stearoyl-CoA desaturase-1 and decreases in phosphorylated acetyl-CoA carboxylase (pACC)/ACC compared with O-CR rats (P < 0.05 for each). The beneficial effects of chronic CR on NAFLD development were largely lost with 4 wk of AL feeding in the hyperphagic OLETF rat, highlighting the importance of maintaining energy balance in the prevention of NAFLD.
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri;
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Linden
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri;
authors.forename: Justin A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri;
authors.forename: Grace M
authors.initials: GM
authors.lastname: Meers
authors.affiliation: Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City, Kansas; and Research Service, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri.
authors.forename: John P
authors.initials: JP
authors.lastname: Thyfault
authors.affiliation: Department of Biomedical Sciences, University of Missouri, Columbia, Missouri;
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; rectors@health.missouri.edu.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
mesh_terms: D000818:Animals; D015415:Biomarkers; D031204:Caloric Restriction; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000178:diet therapy*; D050356:Lipid Metabolism; D050155:Lipogenesis; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF
chemical_list: D015415:Biomarkers; D005227:Fatty Acids
keywords: caloric restriction; de novo lipogenesis; hepatic steatosis; mitochondria