Gender specific differences in metabolism and hypothalamic signaling after short-term high-fat diet

Brain insulin signaling regulates food intake and cognitive function in mammals. During adiposity development, the brain exhibits insulin resistance as early as three days of high fat diet (HFD) feeding, which further results in hyperphagia and obesity development. But most of these effects have always been investigated only in males. Deficiency of insulin receptor in the brain results in more pronounced metabolic effects in females than in males, suggesting a gender-specific difference of brain insulin signaling and metabolism. Here, we investigate gender-specific alterations in metabolism and hypothalamic signaling in mice after a short-term HFD.

We fed C57BL/6N male and female mice at 4 weeks of age a HFD (60% of calories from fat) for 3 days and analyzed body weight, blood glucose levels, plasma triglycerides, non-esterified fatty acids and insulin as well as hypothalamic markers of neuroinflammation and stress markers using qPCR and western blotting techniques.

We show that 3 days of HFD causes only increased body weight and hyperinsulinemia in females but not in males, while males compared to females exhibit already hyperglycemia with unaltered triglycerides and fatty acid levels. In hypothalamus, HFD feeding resulted in exaggerated activation of JNK and IKK in male compared to female mice, but caused a surprising, more pronounced reduction of insulin-responsive stress markers for the endoplasmatic reticulum (Chop), and mitochondria (Hsp60/10) in females.

In conclusion, we identify gender-specific effects of HFD on metabolism, hypothalamic neuroinflammation, metabolic stress responses and insulin-responsive genes, which are enhanced in females and associate with altered metabolism.