Obesity, a condition affecting more than one in three American adults, is associated with hypothalamic neuronal injury, inflammation, and gliosis- a process characterized by accumulation of activated microglia. Experimental evidence from our lab suggests that microglial activation and inflammatory signaling play a functional role in obesity pathogenesis and, furthermore, that this inflammation, or the blockade of such, may affect whole-body glucose homeostasis. Microglial-specific NF-kB knock-out mice are protected from diet-induced obesity, but, despite their lean phenotype, develop glucose intolerance similar to wild type controls. We therefore used stimulatory (hM3Dq) and inhibitory (hM4Di) DREADDs to test the hypothesis that microglial activation or inactivation acutely affects systemic glucose homeostasis. We generated novel mouse models that selectively express the hM3Dq- and hM4Di-DREADD transgenes in microglia. Expression was verified via qRT-PCR, flow cytometry, and IHC. Cohorts of mice and littermate controls were maintained on either normal chow diet or high-fat diet (HFD). Glucose tolerance tests were performed on mice following administration of the DREADD receptor agonist clozapine-N-oxide (CNO). Acute microglial activation via CNO administration in hM3Dq-DREADD animals improved glucose tolerance under both chow and HFD conditions. Acute CNO-induced microglial inactivation in hM4Di-DREADD animals increased fasting glucose in chow-fed animals and worsened glucose tolerance in HFD-fed animals. These findings provide the first evidence that peripheral glucose homeostasis is affected by microglial activity and inflammatory signaling and can be manipulated on an acute timescale using DREADD technology.
K.M. Ness: None. J. Douglass: None. M. Valdearcos-Contreras: None. M.D. Dorfman: None. A. Niraula: None. S.K. Koliwad: Consultant; Self; AstraZeneca. Stock/Shareholder; Self; Suggestic, Yes Health. J. Thaler: None.
National Institutes of Health (T32DK007247, R01DK119754)