Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus

Background

From epidemiology to biomedicine, there is evidence indicating that diet and stress are highly associated. Stress related mental illness, such as post-traumatic stress disorder (PTSD), can influence food intake and body weight, and vice versa. Notably, females and males appear to respond differently to changes in stress levels and diet.

In this preprint, Shetty and colleagues investigated the combined effects of a high fat diet (HFD) and acute stress on behaviour as well as energy metabolism. They further studied mechanisms underlying the sex differences observed in peripheral and central inflammation.

Key findings

1. Sex-dependent relationship between high fat diet and stress

By using HFD or chow diet after foot shocks, Shetty and team found that HFD leads to increased fear extinction in male mice, but not in females. In contrast, chronic stress had no significant impact on blood glucose homeostasis both in male and female. On the other hand, the foot shocks after HFD or chow diet increased energy expenditure of both male and female mice, but different pre-treatment on diet had no effect on fear behavior.

2. Different peripheral and central inflammatory responses in female mice compared to male

Following stress, the pro-inflammatory cytokines IL-1β and IL-12p40 were upregulated in gonadal white adipose tissue, but not in liver. MPP2 cells and downstream cells were significantly reduced in the bone marrow of HFD male mice compared with females.

Results from snRNA-seq of the ventromedial hypothalamus revealed that overall neuroinflammation was comparable between males and females, however different trait genes suggested a difference in astrocytes lipid metabolism. Besides, more active communication between cell types was observed in females than males, including interactions between mature neurons, glutamergic neurons, and tanycytes.

Importance

The well-designed study from Shetty and colleagues, focusing on sex differences in the response to changes in diet and stress, reveals the unique effects of diet and stress on female mice as well as the underlying mechanisms. The two paradigms used, foot-shocks after high fat diet or high fat diet after foot-shocks, followed a specific timeline which revealed the effects of anxiety and high fat diet on metabolism. Although many studies have shown the role of sex in resisting anxiety and obesity, Shetty and team provide more detailed insights in the peripheral and central mechanisms involved.

Future directions

This work provides a fundamental base to better understand fear and obesity and how these influence the central and peripheral mechanisms that regulate energy balance. This work can therefore inspire more research on understanding the mechanisms behind sex differences in behaviour and obesity, including studies focused on uncovering pathways, regulation and possible pharmacological interventions.

Questions for the authors

1. I noted that the mice were in the metabolic chamber for 72 hours, and only the data for the first 12 hours were omitted. Mice will develop anxiety behaviours after changing their living environment. Is 12 hours of adaptation enough to alleviate this effect?
2. Between the two groups of experiments shown in Fig1A (14 weeks) and Fig4A (10 weeks), would it be more accurate to take mice of the same age?

 

 

 

doi: https://doi.org/10.1242/prelights.37952

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