The Thaler Laboratory

Recently, we found that the onset of diet-induced obesity (DIO) in male rodents is associated with hypothalamic inflammation and activation of surrounding astrocytes and microglia (resident CNS macrophages) (Thaler JCI 2012). Our current research focuses on determining the role of the gliosis process in triggering neuronal stress and providing a root cause of high fat diet (HFD)-induced weight gain. We have a variety of ongoing projects investigating the importance of non-neuronal cells in energy homeostasis.

1) Female rodents are relatively DIO-resistant and develop neither hypothalamic inflammation nor brain immune cell (microglia) activation. This protection requires the microglial silencing CX3CL1 receptor (CX3CR1), with CX3CR1 KO females developing DIO and hypothalamic microglial activation like males. Conversely, males treated with CX3CL1 show reduced diet-associated weight gain and microglial activation like females. Together, these data suggest that the CX3CL1-CX3CR1 microglial signaling system can be targeted to reduce DIO susceptibility, support a role for HFD-induced microglial inflammatory activation in obesity pathogenesis, and provide evidence for sexually dimorphic involvement of microglia in metabolism (Dorfman et al, Nature Communications 2017). We are currently  extending these findings by characterizing microglial-neuron crosstalk through CX3CL1-CX3CR1 signaling. In addition, we are pursuing the molecular mechanisms underlying sex differences in gliosis focusing on the role of estrogen receptors in microglial inflammatory activation and, in a productive collaboration with Dr. Ellen Schur, the impact of androgen signaling on gliosis and obesity susceptibility.

2) Hypothalamic inflammation contributes to DIO susceptibility but the source and cell types involved in this inflammation remain poorly understood. Using cutting edge genetic and pharmacological tools, we recently demonstrated that both microglial and astrocytic inflammation via the NF-κB/Ikkβ pathway are required for hyperphagia and weight gain during high fat diet-induced obesity (Douglass et al., Molecular Metabolism 2017; Valdearcos, Douglass, et al. Cell Metabolism 2017). We are now using transcriptomic and candidate-based approaches to elucidate the molecular pathway involved in triggering microglial activation and identify the microglial gene products that effect changes in energy balance.

3) Our previous work describing the role of glial activation in obesity pathogenesis revealed an unexpected divergence in function between microglia and astrocyte inflammatory signaling with regard to glucose metabolism. While astrocyte Ikkβ knockout mice have improved glucose tolerance as expected in thinner animals, microglial Ikkβ knockout mice remained unprotected from obesity-associated glucose dysregulation. Using a novel chemogenetic mouse model, pair-feeding studies, and pharmacological approaches, we have discovered that microglial activation improves glucose handling even while promoting weight gain. We are currently determining the molecular mechanism underlying this surprising finding with the hopes of developing novel diabetes therapeutics.

4) Astrocytes provide fuel substrates for synaptic activity through the glycogenolysis-glycolysis-lactate pathway. We have studied real-time lactate fluctuations in the hypothalamus during feeding and in response to glycogenolysis inhibitors. Current work aims to identify the functional role of astrocyte-derived lactate in feeding behavior using novel chemogenetic and pharmacological methods.