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

• Published in: bioRxiv
• Main Authors: Douglass, John David, Valdearcos, Martin, Ness, Kelly M, Wyse-Jackson, Alice, Dorfman, Mauricio D, Frey, Jeremy M, Niraula, Anzela, Banerjee, Jineta, Fasnacht, Rachael, Robblee, Megan, Koliwad, Suneil K, Thaler, Joshua
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 20.04.2022
• Subjects: Adipose tissue; Body weight; Body weight gain; Chemoreception; Chromium; Clonal deletion; Diet; G protein-coupled receptors; Gene expression; Gliosis; Glucose; Glucose tolerance; High fat diet; Hyperphagia; Hypothalamus; Immunological tolerance; Immunomodulation; Inflammation; Insulin; Insulin resistance; Intolerance; NF-κB protein; Obesity; Tumor necrosis factor-α
• DOI: 10.1101/2022.04.19.488819

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. Competing Interest Statement The authors have declared no competing interest.