While the so-called Western-style diets largely contribute to metabolic dysfunction observed in patients with overweight or obesity, type 2 diabetes mellitus and/or NASH, the current epidemiological evidence suggests that increased consumption of Western-style diets has also a negative impact on cognitive performance1.

In this month’s newsletter, you can view our data that we have presented at the 6th Global NASH Congress earlier in the year. Here, we show that high-fat (HF) and high-fat diet with cholesterol and fructose (HFCF) induce cognitive deficits in mice. 

1Weinstein, Ali A., et al. “Cognitive performance in individuals with non-alcoholic fatty liver disease and/or type 2 diabetes mellitus.” Psychosomatics 59.6 (2018): 567-574.

Following 20 weeks of diet (Chow; HF and HFCF) we observed no differences (A) between the groups in the latency to the first platform visit on each of the 5 acquisition days during Morris Water Maze (MWM) task. However, we repeatedly observed that (B) HF mice performed significantly worse in comparison to Chow-fed mice (Diet effect; HF vs. Chow: Tukey *P=0.019; M±SEM) during the time spent in platform quadrant during the probe trial after acquisition.

During the MWM 4-day reversal trial, we observed that HF diet-fed mice did not differ from Chow and HFCF-fed mice (C). Yet, we repeatedly found that HFCF-fed mice performed significantly worse (D) in comparison to Chow-fed mice (HF vs. Chow: Tukey P=ns; HFCF vs. Chow: Tukey *P=0.023; M±SEM).

We concluded that in comparison to Chow-fed mice, HF-fed mice do not show any spatial memory for the target quadrant, both after initial acquisition and reversal, whereas HFCF-fed mice show a deficit specifically after reversal (D). 

Together, the HF and HFCF-fed mice in combination with the selected cognitive tests constitute a valuable model to investigate the effect of compounds targeting the metabolic system in the setting of chronic metabolic disorders and cognitive performance.

This model is of particular importance when considering that multitude of metabolism-targeting compounds are currently evaluated in the preclinical pipelines. This offers a multi-dimensional perspective, allowing the evaluation of not only the physiological but also behavioural changes.

liver steatosis NASH mouse model CRO liver disease H&E staining

All efficacy studies can be complemented with histopathology readouts. This H&E-stained liver tissue slide shows liver steatosis in NASH mice, graded as stage 3 by our in-house pathologist.

To help you fine-tune your lead compound’s bioavailability, InnoSer has ample experience in carrying out PK/PD studies and analyses. To ensure your compound’s safety, InnoSer can additionally perform safety pharmacology analyses.

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InnoSer provides a variety of validated in vitro and in vivo screening tests for psychiatry and neurology. If you require additional information, feel free to reach out, and we will respond within a few days.

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