title: Consumption of a high-fat diet rapidly exacerbates the development of fatty liver disease that occurs with chronically elevated glucocorticoids.
abstract: Chronically elevated glucocorticoids (GCs) and a high-fat diet (HFD) independently induce insulin resistance, abdominal obesity, and nonalcoholic fatty liver disease (NAFLD). GCs have been linked to increased food intake, particularly energy-dense "comfort" foods. Thus we examined the synergistic actions of GCs and HFD on hepatic disease development in a new rodent model of chronically elevated GCs. Six-week-old male Sprague-Dawley rats received exogenous GCs, via subcutaneous implantation of four 100-mg corticosterone (Cort) pellets, to elevate basal GC levels for 16 days (n = 8-10 per group). Another subset of animals received wax pellets (placebo) to serve as controls. Animals from each group were randomly assigned to receive a 60% HFD or a standard high-carbohydrate (13% fat and 60% carbohydrate) diet. Cort + HFD resulted in central obesity, despite a relative weight loss, a 4-fold increase in hepatic lipid content, hepatic fibrosis, and a 2.8-fold increase in plasma alanine aminotransferase levels compared with placebo + chow controls. Hepatic injury developed independent of inflammation, as plasma haptoglobin levels were reduced with Cort treatment. Insulin resistance and hepatic steatosis occurred with Cort alone; these outcomes were further exacerbated by the HFD in the presence of elevated Cort. In addition to fatty liver, the Cort + HFD group also developed severe insulin resistance, hyperinsulinemia, hyperglycemia, and hypertriglyceridemia, which were not evident with HFD or Cort alone. Thus a HFD dramatically exacerbates the development of NAFLD and characteristics of the metabolic syndrome in conditions of chronically elevated Cort.
authors.affiliation: Muscle Health Research Center and Physical Activity and Chronic Disease Unit, School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada.
authors.forename: Anna M
authors.initials: AM
authors.lastname: D'souza
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Beaudry
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Szigiato
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Trumble
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001284:Atrophy; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D018955:CD36 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D002518:Ceramides / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology*; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D011169:Portal Vein / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018955:CD36 Antigens; D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D003345:Corticosterone