| First Author | Douglass JD | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 9 | Pages | 1613-1629.e8 |
| PubMed ID | 37572666 | Mgi Jnum | J:341129 |
| Mgi Id | MGI:7528553 | Doi | 10.1016/j.cmet.2023.07.008 |
| Citation | Douglass JD, et al. (2023) Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance. Cell Metab 35(9):1613-1629.e8 |
| abstractText | Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor kappaB (NF-kappaB) signaling via cell-specific IKKbeta deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-kappaB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-alpha)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity. |
