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Diabetes 54:1314-1323, 2005
© 2005 by the American Diabetes Association, Inc.
Effects of Diet and Genetic Background on Sterol Regulatory Element-Binding Protein-1c, Stearoyl-CoA Desaturase 1, and the Development of the Metabolic Syndrome
1 Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts
2 Division of Endocrinology, Children’s Hospital, Boston, Massachusetts
3 Department of Biochemistry, University of Wisconsin, Madison, Wisconsin
4 Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin
Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome.
Address correspondence and reprint requests to C. Ronald Kahn, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: c.ronald.kahn{at}joslin.harvard.edu
Abbreviations:
FPLC, fast-performance liquid chromatography; HFD, high-fat diet; LFD, low-fat diet; MUFA, monounsaturated fatty acid; PGC, peroxisome proliferator-activated receptor-
coactivator; SCD, stearoyl-CoA desaturase; SOCS, suppressor of cytokine signaling; SREBP, sterol regulatory element-binding protein
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