Hepatic markers of insulin responsiveness and lipid metabolism are altered by the HFS diets in female mice. Protein and gene expression were assayed in liver by Western blotting (A) and RT-PCR (E). Western blot density quantification is depicted for AKT activation (B), AMPKα activation (C) and fold change of lipid metabolism protein markers (D). Western blot analysis indicates that insulin responsiveness was diminished in livers of HFS-fed mice, with botanical supplementation intensifying this effect (B), as indicated by reduced AKT phosphorylation. Panel (C) shows increased activation of AMPK with botanical supplementation, consistent with increased fatty acid utilization. Expression of CD36, pyruvate dehydrogenase kinase-4 (PDK4), and SCD-1 proteins (D) was altered by each HFS diet compared to the LFD. Hepatic mRNA expression of cd36, scd-1, and pck-1 was significantly altered by the HFS diets (E). Hepatic triglyceride levels were increased by the HFS diet but not in the HFS diet supplemented with bitter melon or PMI5011 (E). Liver function was not affected by the HFS in the females (G). Statistical significance was set at * p < 0.05, ** p < 0.01, *** p < 0.001 compared to LFD (B–E); variability is expressed as mean ± SD. n = 3 (A–D); n = 5 (E–G).