Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

Abstract

Hypothalamic gliosis associated with high fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain, and is therefore presumed to promote obesity-associated consequences such as glucose intolerance as well. Nevertheless, the body weight-independent contribution of microglial activation to glucose regulation has not been determined. Here we show that reducing microglial NF-κB signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance and insulin resistance despite reducing body weight and adiposity. This effect was associated with reduced activity of hypothalamic glucose sensing neurons. Conversely, a genetic approach to increase microglial inflammatory activity improved glucose tolerance independently of diet in lean rodents. To avoid confounding effects due to chronic alterations to microglial signaling pathways from dietary or genetic interventions, we developed an inducible model of microglial activation using DREADD-based chemogenetics. Gq-coupled GPCR activation rapidly increased microglial calcium levels, cytokine gene expression, and morphological hallmarks of inflammatory activation. In both lean and obese rodents, chemogenetic microglial activation caused a marked improvement in glucose tolerance along with increased activation of hypothalamic glucose sensing neurons, effects abrogated by central blockade of TNFα signaling. Thus, while diet-induced microglial activation promotes weight gain, it may also serve an adaptive function—to prevent the deterioration of glucose tolerance associated with obesity, an important consideration for immune-modulating metabolic therapies.

Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience

“…A recent study (preprint) has unexpectedly shown that microglial inflammation, induced by Gq‐DREADD activation, improved glucose tolerance, both in lean and obese mice. This effect depended on TNF‐α signaling in microglia, which increased the activity of hypothalamic glucoresponsive neurons (Douglass et al, 2022). Glucose intolerance is also observed in other diseases as diabetes mellitus (Malone & Hansen, 2019), chronic kidney disease (Spoto et al, 2016), and cystic fibrosis (Kasim et al, 2021).…”