Abstract
Early hyperphagia and hypothalamic inflammation encountered after Western diet (WD) are linked to rodent propensity to obesity. Inflammation in several brain structures has been associated with gut dysbiosis. Since gut microbiota is highly sensitive to dietary changes, we hypothesised that immediate gut microbiota adaptation to WD in rats is involved in inflammation-related hypothalamic modifications. We evaluated short-term impact of WD consumption (2 h, 1, 2 and 4 days) on hypothalamic metabolome and caecal microbiota composition and metabolome. Data integration analyses were performed to uncover potential relationships among these three datasets. Finally, changes in hypothalamic gene expression in absence of gut microbiota were evaluated in germ-free rats fed WD for 2 days. WD quickly and profoundly affected the levels of several hypothalamic metabolites, especially oxidative stress markers. In parallel, WD consumption reduced caecal microbiota diversity, modified its composition towards pro-inflammatory profile and changed caecal metabolome. Data integration identified strong correlations between gut microbiota sub-networks, unidentified caecal metabolites and hypothalamic oxidative stress metabolites. Germ-free rats displayed reduced energy intake and no changes in redox homoeostasis machinery expression or pro-inflammatory cytokines after 2 days of WD, in contrast to conventional rats, which exhibited increased SOD2, GLRX and IL-6 mRNA levels. A potentially pro-inflammatory gut microbiota and an early hypothalamic oxidative stress appear shortly after WD introduction. Tripartite data integration highlighted putative links between gut microbiota sub-networks and hypothalamic oxidative stress. Together with the absence of hypothalamic modifications in germ-free rats, this strongly suggests the involvement of the microbiota-hypothalamus axis in rat adaptation to WD introduction and in energy homoeostasis regulation.
Highlights
Obesity is the consequence of prolonged disruption of energy homeostasis and hedonic/reward control of appetite 1, mainly regulated by the coordinated action of many brain regions including the brainstem, the hypothalamus and cortical or subcortical brain areas 1
First week energy intake after dietary switch to Western diet (WD) was predictive of long-term obesity parameters
First week energy intake was positively correlated to fasted glycemia (Fig. 1E) and plasma Lipopolysaccharides Binding Protein (LBP) (Fig. 1F) measured at week 6. The intensity of this phase of increased energy intake upon dietary switch to WD seems predictive of later obesity parameters and of metabolic and systemic inflammatory parameters
Summary
Obesity is the consequence of prolonged disruption of energy homeostasis and hedonic/reward control of appetite 1, mainly regulated by the coordinated action of many brain regions including the brainstem, the hypothalamus and cortical or subcortical brain areas 1. The hypothalamus integrates internal peripheral signals mostly from the gastro-intestinal tract as well as from adipose tissue or pancreas 2 It integrates brainstem information originating from the vagus nerve and circulating peripheral signals to adapt energy intake and/or energy expenditure. Long-term consumption of a Western diet (WD), i.e. a low-fiber, high fat and sugar diet, as opposed to a well-balanced diet (chow), leads to the development of obesity and metabolic disorders. This long-term condition is preceded by an asymptomatic period characterized by metabolic and behavioral adaptations to the acute dietary switch from chow to WD 7. Since gut microbiota is highly sensitive to dietary changes, we hypothesized that immediate gut microbiota adaptation to WD in rats is involved in inflammationrelated hypothalamic modifications
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