Hepatomegaly and liver gene expression data suggest hepatic insulin resistance is most severe for Mc4rKO. Mc4rKO demonstrate marked hepatic steatosis and hepatomegaly compared with Mc3rKO and WT. A, Hematoxylin and eosin-stained cross-sections of liver tissue from female Mc4rKO, Mc3rKO, and WT mice fed a high-fat diet. B, Plot of liver weight vs. adiposity from several studies where mice were fed low- or high-fat diets. C, Mean liver weight of female Mc4rKO, Mc3rKO, and WT mice fed a moderately high-fat diet. Mc4rKO also exhibited generally increased lipogenic gene expression compared with both Mc3rKO and WT mice (n = 5–6 per group). D and E, Expression of stearoyl-CoA desaturase 1 (Scd1) (D), and apolipoprotein A4 (Apoa4) (E) in the liver of WT, Mc3rKO, and Mc4rKO fed the high-fat diet. Data are expressed as arbitrary units (a.u.). *, P < 0.05 vs. WT and Mc3rKO; #, P < 0.05 vs. WT mice, within gender.