Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.
OBJECTIVE
This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse.


METHODS
Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR.


RESULTS
MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR.


CONCLUSIONS
Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.
Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring-on-Hudson, NY 10516, USA. Electronic address: vmalloy@orentreich.org.
Virginia L
VL
Malloy
Carmen E
CE
Perrone
Dwight A L
DA
Mattocks
Gene P
GP
Ables
Nicholas S
NS
Caliendo
David S
DS
Orentreich
Norman
N
Orentreich
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006706:Homeostasis; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000172:deficiency*; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000008:administration & dosage* / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D012720:Severity of Illness Index; D014280:Triglycerides / Q000097:blood
D015415:Biomarkers; D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D020738:Leptin; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008715:Methionine; D020155:3-Hydroxybutyric Acid
ALT; AST; Acac; Acadvl; Adiponectin; ApoB; C-C chemokine receptor-2; CF; Ccr2; Cd 36; Chrebp; Cpt1a; Dgat; EGF-like module-containing mucin-like hormone receptor-like 1; Emr1; FAO; FFA; Fasn; Fatty acid oxidation; Fatty liver; GSH; Gpam; HDL; HFD; HMW; HOMA; Hadha and Hadhb; IL6; IR; Inflammation; Itgax; LDL; Lxr; MR; Mttp; NAFLD; NASH; Pklr; Pnpla2; Pnpla3; Pparα; Pparγ; ROS; Scd1; Srebf1; TG; TNF-α; Triglyceride; VLDL; acetyl-CoA carboxylase; acyl-coenzyme A dehydrogenase, very long chain; alanine aminotransferase; apolipoprotein B; aspartate aminotransferase; carbohydrate regulatory binding protein; carnitine palmitoyltransferase-1a; control-fed; diacylglycerol O-acyltransferase; fatty acid oxidation; fatty acid synthase; free fatty acids; glutathione; hepatic CD36 antigen; high-density lipoprotein; high-fat diet; high-molecular-weight; homeostasis model assessment; hydroxyacyl-coenzyme A dehydrogenase/3-ketoacyl-coenzyme A thiolase/enoyl-coenzyme A hydratase (trifunctional protein), alpha and beta subunits, respectively; insulin resistance; integrin alpha X; interleukin-6; liver X-receptor; low-density lipoprotein; methionine restriction; microsomal triglyceride transfer protein; mitochondrial glycerol-3-phosphate acyltransferase; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; ob/ob; obese mouse; patatin-like phospholipase domain containing 2; patatin-like phospholipase domain containing 3; peroxisome proliferator-activated receptor α; peroxisome proliferator-activated receptor γ; pyruvate kinase-liver and red blood cell; reactive oxygen species; stearoyl-coenzyme A desaturase-1; sterol regulatory element binding transcription factor 1; triglycerides; tumor necrosis factor-α; very-low-density lipoprotein