Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding

Abstract

Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after highfat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microglia activation is ill defined. Here, we show that in vivo, HFD induced a rapid and transient increase in uncoupling protein 2 (Ucp2) mRNA expression together with changes in mitochondrial dynamics. Selective microglial deletion of Ucp2 prevented changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation. In association with these, male and female mice were protected from HFD-induced obesity, showing decreased feeding and increased energy expenditure that were associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. Together, our data point to a fuel-availability-driven mitochondrial mechanism as a major player of microglia activation in the central regulation of DIO.

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

“…As previously described, HFD-induced hypothalamic inflammation is associated with glial reactivity (Balland and Cowley, 2017; Baufeld et al, 2016; Buckman et al, 2015; Gao et al, 2014; Guillemot-Legris et al, 2016; Kim et al, 2019; Milanova et al, 2019; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014; Waise et al, 2015). First, we focused on GFAP-positive cells.…”

“…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).…”

“…It seems certain that long-term exposure to HFD induces chronic low-grade systemic inflammation, which is responsible for the development of insulin resistance, type 2 diabetes mellitus along with other chronic illnesses such as cardiovascular disease or cancer (Cani et al, 2007; Emerson et al, 2017; Ghanim et al, 2009; Herieka and Erridge, 2014; Kelly et al, 2012; Lumeng and Saltiel, 2011; Thaler and Schwartz, 2010). More recently, hypothalamic inflammation, a process involving neurons, astrocytes and microglia, has been correlated with obesity and chronic HFD consumption (Balland and Cowley, 2017; Baufeld et al, 2016; Buckman et al, 2015; Gao et al, 2014; Guillemot-Legris et al, 2016; Kim et al, 2019; Milanova et al, 2019; Thaler and Schwartz, 2010; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014), underlining the effect of chronic exposure to HFD on the central inflammatory status. Interestingly, brain inflammatory responses in the HT were also observable after only one day of HFD consumption (Buckman et al, 2015) or 24h of lipid perfusion to the brain (Dalvi et al, 2017), well before the development of obesity.…”

“…Since 2012, several studies have shown that HFD consumption induces astrogliosis and microgliosis in the arcuate nucleus (ARC) of the HT (Andre et al, 2017; Balland and Cowley, 2017; Baufeld et al, 2016; Gao et al, 2014; Guillemot-Legris et al, 2016; Kim et al, 2019; Thaler et al, 2012; Valdearcos et al, 2017; Valdearcos et al, 2014). The microglia activation that is induced by lipids and connects dietary fat and brain inflammatory signaling is begging to be seen as the missing link between the hypothalamic response to HFD and susceptibility to obesity (Andre et al, 2017; Kim et al, 2019; Valdearcos et al, 2017; Valdearcos et al, 2014). Nevertheless, it has recently been shown that HFD-induced inflammation in astrocytes may have a protective effect against the development of obesity (Buckman et al, 2015).…”

“…Nevertheless, it has recently been shown that HFD-induced inflammation in astrocytes may have a protective effect against the development of obesity (Buckman et al, 2015). Interestingly, hypothalamic inflammation has been described very early in response to HFD, before the onset of obesity (Balland and Cowley, 2017; Buckman et al, 2015; Kim et al, 2019; Thaler et al, 2012; Waise et al, 2015). Exposure to HFD for a 24h period increases gene expression of inflammatory astrocyte and microglia markers as well as astrogliosis in the HT (Buckman et al, 2015; Dalvi et al, 2017; Thaler et al, 2012).…”