Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function

Abstract

Diets rich in saturated fat produce inflammation, gliosis, and neuronal stress in the mediobasal hypothalamus (MBH). Here we show that microglia mediate this process and its functional impact. Although microglia and astrocytes accumulate in the MBH of mice fed a diet rich in saturated fatty acids (SFAs), only the microglia undergo inflammatory activation, along with a build-up of hypothalamic SFAs. Enteric gavage specifically with SFAs reproduces microglial activation and neuronal stress in the MBH, and SFA treatment activates murine microglia, but not astrocytes, in culture. Moreover, depleting microglia abrogates SFA-induced inflammation in hypothalamic slices. Remarkably, depleting microglia from the MBH of mice abolishes inflammation and neuronal stress induced by excess SFA consumption, and in this context, microglial depletion enhances leptin signaling and reduces food intake. We thus show that microglia sense SFAs and orchestrate an inflammatory process in the MBH that alters neuronal function when SFA consumption is high.

Glial cells and energy balance

“…The effects of long-chain saturated FAs are seen in both astrocytes and microglia, where they induce the release of inflammatory molecules. In contrast, this inflammation does not occur in response to non-saturated FAs (Milanski et al 2009, Gupta et al 2012, Morselli et al 2014, Valdearcos et al 2014. Thus, the astrocytic signals released to the surrounding neurons depend on the specific type of nutrient perceived by these cells and this in turn most likely affects neuronal metabolic sensing.…”

“…Indeed, numerous studies in animals have shown evidence of inflammation/gliosis in response to HFD (Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, whereas this has also been reported to occur in humans with an elevated body mass index (BMI) (Thaler et al 2012). However, hypothalamic glial cells not only participate in pathological events, such as the inflammatory response that occurs as a consequence of HFD consumption (Milanski et al 2009, Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, Yan et al 2014), but they are also intricately involve in the physiological control of the surrounding neurons, including those dictating energy balance.…”

“…Indeed, numerous studies in animals have shown evidence of inflammation/gliosis in response to HFD (Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, whereas this has also been reported to occur in humans with an elevated body mass index (BMI) (Thaler et al 2012). However, hypothalamic glial cells not only participate in pathological events, such as the inflammatory response that occurs as a consequence of HFD consumption (Milanski et al 2009, Thaler et al 2012, Buckman et al 2014, Valdearcos et al 2014, Yan et al 2014), but they are also intricately involve in the physiological control of the surrounding neurons, including those dictating energy balance. The importance of this relationship is even further emphasized by the fact that these glial cells express receptors and systems of transport for numerous metabolic hormones and factors (Boyles et al 1985, Vielkind et al 1990, Zhu et al 1990, Vannucci et al 1997, Marty et al 2005, Pan et al 2008, Hsuchou et al 2009, Baquedano et al 2013, suggesting that at least part of the central effects of these metabolic signals are mediated through these non-neuronal cells.…”

“…Studies indicating that the activation of hypothalamic glial cells in response to high-fat diet (HFD) intake is involved in central inflammation and insulin resistance have drawn increasing attention to the role that these cells play in metabolic control (Thaler et al 2012, Buckman et al 2013, Valdearcos et al 2014). …”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Moreover, the inhibition of TLR4 can also attenuate diet-induced ERS, suggesting that TLR4 is upstream of ERS in obesity-associated hypothalamic inflammation (15). However, studies have demonstrated that ERS is also an important component of the inflammatory activity of the hypothalamus in obese animals and the inhibition of ERS with chemical chaperones is capable of reducing the impact of dietary fats in the anomalous regulation of hypothalamic neurons involved in energy homeostasis (16,36). Figure 1 shows a current view of the mechanism and cells involved in diet-induced hypothalamic inflammation.…”