Obesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and activation of microglia, the resident CNS immune cells. Recently, we provided evidence that microglia are critical intermediary cells that transmit the inflammatory signal induced by HFD exposure. Mice with a conditional knockout of IKKb specifically in microglia (CX3CR1CreERT2 x IKKbeta fl/fl, MGKO) have reduced susceptibility to HFD-associated hyperphagia and DIO compared with IKKb fl/fl littermate controls (Ctl). Surprisingly, despite their reduced fat mass, HFD-fed MGKO mice have equal glucose intolerance to Ctls as well as no improvement in white adipose tissue inflammation or hepatic triglyceride content. Together these data suggest dissociation between microglial regulation of energy and glucose homeostasis. To address this possibility, we pair-fed MGKO mice to Ctl mice, resulting in matched body weights during HFD feeding. Pair-fed MGKO mice showed a greater degree of impairment in glucose tolerance and insulin sensitivity with preserved insulin secretion compared to controls. Similarly, chemical inactivation of microglia using centrally-administered minocycline worsens insulin sensitivity in HFD-fed rats. Finally, using several distinct genetic models, we show that microglial activation acutely improves glucose tolerance and insulin sensitivity. Together, these data reveal a novel aspect of CNS regulation of metabolism in which microglial inflammatory activation promotes HFD overconsumption and weight gain but offsets obesity-associated dysregulation of glucose homeostasis. These results indicate the need for pathway-specific targeting to develop glial-based therapeutics for obesity and diabetes.
J. Douglass: None. M. Valdearcos: None. S.K. Koliwad: None. J. Thaler: Research Support; Self; Novo Nordisk A/S.