Discovering new brain-based treatments for obesity and diabetes
Obesity remains a leading public health problem due to its association with diabetes, heart disease, cancer and other significant chronic illnesses. Currently, over 2/3 of US adults are overweight or obese, perpetuated by an environment that promotes unhealthy eating habits and sedentary behavior. Unfortunately, over the twenty years since the discovery of the adiposity hormone leptin and the characterization of its action in the hypothalamus to regulate energy homeostasis, few effective obesity treatments have been developed. This failure of progress highlights the difficulties inherent in a “neurocentric” approach to pharmacotherapy (limited CNS bioavailability, undesired neuropsychiatric side effects, and neural network compensation). Thus, new approaches to obesity pathogenesis are urgently needed.
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 (Submitted to Cell Metabolism, Apr 2016). Current work focuses on determining the molecular changes in microglial-neuron crosstalk induced by CX3CL1-CX3CR1 signaling.
2) Hypothalamic inflammation contributes to DIO susceptibility through increased neuronal leptin resistance but the source of this inflammation is unknown. We are currently testing whether either microglial or astrocytic inflammation via the NF-κB/Ikkβ/TNFα pathway is essential for hypothalamic inflammation and DIO using recently-developed genetic and pharmacological tools.
3) Astrocytes also 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.
Our work is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the American Heart Association, and the American Diabetes Association.
UW Diabetes Institute
University of Washington School of Medicine
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