Upstream regulators analysis (Table 3) indicated the presence of factors potentially involved in the modulation of altered pathways in our analysis: besides the activation of Insr, Igf1r and Essra, which are well known critical and protective factors in regulating metabolic homeostasis and insulin sensitivity [68,69], Ppargc1a and Ppargc1b were activated, while Cpt1b, Clpp, Tp53 and Kdm5a inhibited in females under both 45% and 60% HFDs, contributing to improving glucose tolerance and counteracting insulin resistance. The gene discussed is CLPP; the disease is Insulin resistance.