Dietary sugars, not lipids, drive hypothalamic inflammation

Abstract

ObjectiveThe hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear.MethodsWe dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM).ResultsWe found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet.ConclusionsCombined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.

Fat food exacerbates post-prandial hypothalamic inflammation involving GFAP+ cells and microglia

“…Given the lack of a peripheral inflammatory response in HFD-fed mice, we subsequently investigated the impact of a HFD on hypothalamic inflammatory markers. Consistent with previous studies (Andre et al, 2017; Baufeld et al, 2016; Buckman et al, 2015; Gao et al, 2017; Gao et al, 2014; Guillemot-Legris et al, 2016; Nadjar et al, 2017; Thaler and Schwartz, 2010; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014) we found that gene expression of the pro-inflammatory cytokine genes IL1β, IL6 and TNFα, as well as chemokine genes CCL2 and CCL5 was significantly increased in HFD-fed mice compared to SD-fed mice (Fig. 2A-E).…”

“…In our study, the calories from fat and sugar in HFD were equivalent (40% each), in contrast to numerous studies where fat content accounts for 60% kilocalories (kcal) while carbohydrate content was only 20% kcal. Therefore, the increase in caloric proportion represented by the lipids is more realistic in our model, and comparable to the typical human diet, where the occurrence of lipids in the presence of elevated carbohydrate content contributes to brain inflammation (Andre et al, 2017; Gao et al, 2017; Kim et al, 2019). According to previous studies of systemic post-prandial inflammation, HFD consumption promotes lipopolysacharide trafficking over the intestinal epithelium through trans-cellular and para-cellular transport (Valdearcos et al, 2014; Buckman et al, 2015).…”

“…In addition to astrogliosis, hypothalamic inflammation after medium-term (3 to 7 days) and long-term (2 to 20 weeks) HFD exposure is also associated with microgliosis (Andre et al, 2017; Baufeld et al, 2016; Dorfman et al, 2017; Gao et al, 2017; Gao et al, 2014; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014). As for astrocytes, we tested whether short-term exposure (1h, 3h and 6h) to HFD might affect microglial cells in the HT.…”

“…5A). We then tested whether Iba1 gene upregulation impacted Iba1 protein levels in the ARC, as previously described for medium term and long term HFD exposure (Andre et al, 2017; Baufeld et al, 2016; Dorfman et al, 2017; Gao et al, 2017; Gao et al, 2014; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014). No change in Iba1 immunofluorescence staining was observed (Fig.…”

“…Overall, while the effect of medium-term and long-term nutritional lipid exposure has been extensively demonstrated to promote hypothalamic inflammation involving astrocytic and microglial cells (Andre et al, 2017; Balland and Cowley, 2017; Baufeld et al, 2016; Gao et al, 2017; Gao et al, 2014; Guillemot-Legris et al, 2016; Nadjar et al, 2017; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014), little was known about short-term exposure. Here we demonstrate, for the first time, that a moderate increase of nutritional lipid content in diet – representative of current human diets – can exacerbate hypothalamic post-prandial inflammation in a short time and that this response involves hypothalamic GFAP-positive cells and microglial cells.…”