The present data showed that the earliest alteration upon HFHS dieting (at 1-week) was up-regulation of SOCS3 in hypothalamus and liver, which coincided with the onset of hyperinsulinemia, hyperglycemia, elevated hepatic TG and cholesterol, down-regulation of OBR, and attenuated insulin receptor activation. Here, SOCS3 is linked to hyperinsulinism.