During repeated preparations of high-fat diet (HFD)-induced obese mice, we have reproducibly observed both obesity-resistant (HFDlean) and obesity-prone (HFDfat) subpopulations in ddY mice, an outbred strain. To investigate metabolic characteristics of the subpopulations, we analyzed liver gene expression and glucose- and fat metabolisms. Hepatic steatosis was attenuated in HFDlean even after ingestion of HFD for 15 weeks, whereas HFDfat formed severe fatty liver. HFDlean showed normal glucose tolerance and insulin sensitivity, whereas HFDfat showed severe diabetes. Expression of genes for fatty acid transport (CD36), cytoplasmic triglyceride synthesis (DGAT2), fat synthesis (SREBP-I, PPARγ, PPARα) and β-oxidation (CPT-1a, acyl CoA oxidase) were significantly attenuated in HFDlean as compared with those in HFDfat. Low expression of apoB and MTP in HFDlean consisted with their lower plasma LDL concentration. Also, plasma leptin concentration and liver β2 adrenoceptor (β2AdR) expression were significantly low, and hepatic glycogen content of HFDlean was higher than that of HFDfat. These results suggest that lower hepatic steatosis of HFDlean was due to the decreased incorporation of fatty acid into the liver and suppression of triglyceride synthesis therein; and that inefficient glycogenolysis by less sympathetic activation in the liver of HFDlean.

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