A Complex Interaction Between Diet and Genetic Predisposition to Obesity and Type 2 Diabetes Modulates Behavioral Phenotypes in Mice (P14-014-19)

Abstract

Abstract Objectives The aim of the study was to compare the locomotor, exploratory activities, anxiety-related behavior, and expression levels of the low density lipoprotein-related protein 1B (Lrp1b) gene in the brain of obese diabetic TALLYHO/Jng (TH) and lean C57BL/6 J (B6) mice fed high fat diets (HFD) and chow. Methods Male and female TH and B6 mice were weaned onto chow or HFD and maintained. At 5 and 16 weeks of age (wk), mice were subjected to three behavioral tests; open field, grip strength and rota-rod. At 20 wk, mice were killed and the hypothalamus, neocortex, hippocampus, and cerebellum dissected. Results In the open field, total distance traveled was lower in TH vs. B6, and HFD further reduced distance traveled for TH but not B6 at both 5 and 16 wk. There was no effect of sex. At 16 wk, HFD significantly increased time spent in the edge zone of the open field, suggesting an increase in anxiety, regardless of strain or sex. Also, TH mice spent more time in the edge zone, indicating a strain difference independent of either sex or diet. HFD significantly decreased the amount of time spent in the center zone of the open field, potentially suggesting a decrease in exploratory behavior, regardless of strain or sex. For the rota-rod test, male B6 on HFD and female B6 on both diets showed equivalent high performance, whereas the remaining groups showed equivalent low performance at 5 wk. At 16 wk, the only significant effect was for strain, with B6 showing better rota-rod performance than TH. For grip strength, TH mice showed greater strength than B6. HFD reduced grip strength for male, but not female B6, whereas HFD increased it for TH mice. While there were strain and sex differences in body weight, HFD had no effect on weight at 5 wk, whereas, there were significant effects of diets on weight at 16 wk. In both TH and B6 mice, the Lrp1b gene was expressed most highly in the neocortex. Neocortical Lrp1b gene expression was increased twofold by HFD, with no strain differences. LRP1B protein levels showed a similar pattern. Conclusions Behavioral testing has shown a complex interaction between strain, sex, and diet; the effects of diet at 5 wk are independent of body weight. Lrp1b is highly expressed in the neocortex and up-regulated by obesity-inducing HFD. Funding Sources WVCTSI pilot grant, AHA 18UFEL33960330, AHA 18AIREA33960437, NIH 1 R15 DK113604–01A1.