Diet, sex, and genetic predisposition to obesity and type 2 diabetes modulate motor and anxiety-related behaviors in mice, and alter cerebellar gene expression.

Obesity and type 2 diabetes (T2D) are serious health problems linked to neurobehavioral alterations. We compared motor function, anxiety-related behavior, and cerebellar gene expression in TALLYHO/Jng (TH), a polygenic model prone to insulin resistance, obesity, and T2D, and normal C57BL/6 J (B6) mice. Male and female mice were weaned onto chow or high fat (HF) diet at 4 weeks of age (wk), and experiments conducted at young (5 wk) and old (14 - 20 wk) ages. In the open field, distance traveled was significantly lower in TH (vs. B6). For old mice, anxiety-like behavior (time in edge zone) was significantly increased for TH (vs B6), females (vs males), and for both ages HF diet (vs chow). In Rota-Rod testing, latency to fall was significantly shorter in TH (vs B6). For young mice, longer latencies to fall were observed for females (vs males) and HF (vs chow). Grip strength in young mice was greater in TH (vs B6), and there was a diet-strain interaction, with TH on HF showing increased strength, whereas B6 on HF showed decreased strength. For older mice, there was a strain-sex interaction, with B6 males (but not TH males) showing increased strength compared to the same strain females. There were significant sex differences in cerebellar mRNA levels, with Tnfα higher, and Glut4 and Irs2 lower in females (vs males). There were significant strain effects for Gfap and Igf1 mRNA levels with lower in TH (vs B6). Altered cerebellar gene expression may contribute to strain differences in coordination and locomotion.