First person – Payel Kundu

Payel Kundu

How would you explain the main findings of your paper to non-scientific family and friends?

Eating a diet high in fat has been linked to obesity, metabolic dysfunction and cognitive impairment. In our research, we've found that xanthohumol (XN), a substance found in the hops plant, dramatically improves metabolic parameters and cognition in obese mice, even if the mice don't lose weight. We know that XN modulates the activity of the farnesoid X receptor (FXR), the primary receptor family for bile acids. We hypothesized that this may be one of the mechanisms by which XN confers beneficial cognitive effects in obese mice. In this study, we fed mice a high-fat diet or a high-fat diet with XN, and investigated the effects on cognition in wild-type mice as well as mice lacking FXR receptors in either their intestines or livers. In this way, we hoped to find out if XN is acting through FXR receptors in either organ to improve cognition in obese mice, and, if so, which population of FXR receptors was responsible for the effect. FXR activation plays a role in insulin sensitivity, carbohydrate metabolism, and hepatic triglyceride homeostasis, and so is an attractive therapeutic target for improving metabolic outcomes. We found that XN improved cognition and metabolic parameters in the brain, but in a sex- and genotype-dependent manner. Specifically, XN improved task learning in wild-type female mice, and cognitive flexibility in wild-type and FXR-intestine-knockout male mice, and these beneficial changes were associated with higher diacylglycerol and lower long-chain ceramide and hexaceramide levels. Importantly, XN treatment did not significantly improve impaired cognition of high-fat diet-fed mice with FXR knocked out in the liver, indicating that FXR receptors in the liver may be an important mediator of XN's beneficial cognitive effects. Our work highlights the importance of including males and females in medical research, and supports the therapeutic potential of XN to ameliorate metabolic and cognitive dysfunction associated with consumption of a high fat diet.

What are the potential implications of these results for your field of research?

Our body of work with XN indicates that, even in the absence of weight loss, XN holds promise to ameliorate the metabolic and cognitive dysfunction associated with chronic consumption of a high-fat diet. In this study, we elucidated a potential pathway for XN's beneficial cognitive effects, through FXR receptors in the liver, which also suggests that dysfunctional signalling through this receptor may be a mechanism by which a high-fat diet impairs cognition. In addition, we found that higher diacylglycerol and lower long-chain ceramide and hexaceramide levels were associated with improved cognitive performance, which also reveals new targets for therapeutic intervention for high-fat-diet-induced cognitive impairment.

What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?

The experimental system used in this project has several strengths. The compound we tested, XN, has an excellent safety profile, with no detectable toxicity in mice treated with doses of up to 1000 mg/kg. Additionally, we used mice with intestine- and liver-specific FXR ablation, allowing a fine-grained analysis of which population of FXR receptors XN is likely to confer cognitive benefits through. XN was administered to the mice orally, mixed with their diet, thus allowing XN to be metabolized in a clinically relevant way and go through first-pass hepatic metabolism. The cognitive test we used, the Morris water maze, includes the measurement of several different cognitive modalities, including cue learning, spatial learning and reversal learning, allowing us to investigate cognitive effects of XN in a multi-faceted way. We characterized the lipid profile in the hippocampus, a key brain area for learning and memory, with fine acuity by individually measuring lipids of great clinical relevance including diacylglycerol, sphingomyelin, ceramides and hexaceramides. Importantly, we then correlated these lipid levels in the brain with various aspects of cognitive performance, gleaning meaningful insights into the roles of these lipids on brain health. Finally, we included both males and females in this study, and indeed found substantial sex differences in both cognitive performance and hippocampal lipid profiles, highlighting the need to include both sexes in medical research studies.

Limitations of the present work include the fact that it is a study in rodents. Future studies in humans are warranted to investigate if the same metabolic pathways are involved in high-fat-diet-induced cognitive impairment in humans. Additionally, the Morris water maze trial in this study was shorter than the one used in our previous study. This may have prevented us from seeing XN-induced improvements in spatial memory in this study, in contrast to our previous work using the longer training paradigm.

What has surprised you the most while conducting your research?

One thing that surprised me was the fact that XN can dramatically improve metabolic and cognitive outcomes in mice fed a high-fat diet, even in the absence of weight loss! That suggests that obesity is separable from metabolic dysfunction to some extent, and thus affects how we approach metabolic syndrome and diet-induced cognitive impairment therapeutically. As losing weight can be challenging, this is definitely welcome news. Another thing that surprised me was how quickly rodents can be induced to develop dysfunctional metabolism on a high-fat diet. As little as 5 weeks of eating a diet high in saturated fat significantly alters serum lipid and glucose profiles and body weight. This is really a wake-up call on how important it is to try to maintain a healthy diet. I've also been very surprised by the robust sex differences we've seen in cognition and responses to therapeutic interventions for metabolic dysfunction by XN, reiterating to me how important it is to include both sexes in medical research.

What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?

One of the most significant challenges in this line of research is the limitation of using translational models for diet-induced obesity that recapitulate some important aspects, but not all aspects, of metabolic dysfunction in humans. I co-authored a review on this topic in 2021 (Zimmerman et al., 2021). For example, rodent models readily develop cognitive dysfunction on a high-fat diet, even if that fat comes from polyunsaturated fatty acids; however, in large human studies, this has not been found, indicating there may be important differences in how rodents and humans process dietary fat. Humans on a high-fat diet that is low in carbohydrates have better cardiovascular and metabolic outcomes than calorie-matched individuals on a high-carbohydrate diet. This is true even if the diet is high in saturated fat and in the absence of weight loss. However, mice consuming a high-fat diet with zero carbohydrate content more readily become obese compared to mice consuming standard chow, even though the two groups consume a similar number of total calories. These mice develop a metabolic profile similar to that seen in humans consuming a high-carbohydrate diet, including increased fat deposits in the liver and heart, impaired glucose regulation and insulin resistance. As we understand more about these cross-species differences, it will be possible to create ever more translationally relevant models with the use of transgenic mouse models and diets that faithfully recapitulate the dysfunctional metabolic pathways seen in humans. The growing ease and cost effectiveness of CRISPR-Cas9-based gene editing and genome-wide association study technologies will no doubt aid in the goal of identifying loci of interest in humans and translating that into rodent and other animal models.

What changes do you think could improve the professional lives of scientists?

In Nature's 2022 global survey of graduate students, only 62% of graduate students said they were satisfied with their current programme. Even pre-pandemic, the number was only 71%. These surveys provide important insight into what is working well in graduate programmes, and what needs to be revaluated and improved. Students' top categories of concern were maintaining work-life balance, financial stress and career prospect uncertainty. Thus, these are the areas most in need of improvement. It is important for students and fellows to know the expectations about working hours and goals before they begin academic programs. It is also important to assure sufficient support for mental health resources like counselling and stress management for students. As done at Oregon Health and Science University (OHSU) and other institutions, stipends should be increased for students in areas where cost of living outstrips the stipend amount. Ideally, subsidized housing would be made available to more students and postdocs living in relatively expensive cities. Finally, recognizing that there are simply not enough positions in academic science to house the number of graduating PhDs, courses around alternative career pathways, as organized in the Department of Neuroscience at OHSU, are critical to connect students with scientific training and networks outside of academia.

What's next for you?

I am now a scientist conducting human health-related risk assessment in various contexts. This sometimes involves chemicals in the food we eat or the water we drink, exposures to volatile compounds in ambient air, or substances present in personal care products. I am pursuing my passion for improving human health through science, and my scientific training as a PhD student and a postdoc has proved hugely valuable to the work I now do. I plan to continue to grow in my scientific independence and knowledge, and I hope to progress in my career so I can mentor young scientists and create a culture of respect, balance and passionate interest in the work we do.