Obesity is a significant public health concern worldwide, and the incomplete understanding of its pathogenesis has limited the development of effective treatments. Overnutrition triggers immune cell activation in peripheral tissues and the brain, suggesting that strategies to target the inflammatory response have theoretical therapeutic potential. However, these approaches remain largely untested. We recently demonstrated that mice lacking IKK? in brain glia (astrocytes and microglia) show reduced susceptibility to diet-induced obesity (DIO) and hyperphagia, but with different kinetics. Microglial activation occurs earlier and is required for DIO susceptibility from the onset of HFD feeding whereas astrocyte protection from DIO only occurs after weeks of HFD exposure. Consistent with the known role of microglia to induce reactive astrocytosis in CNS inflammatory diseases, these data suggest a cascade of inflammatory activation beginning with microglia that subsequently triggers astrocytes to promote DIO. Another stark difference between the mouse models is a paradoxical impairment of glucose tolerance in the lean microglial IKK? knockout, suggesting dissociation between the regulation of energy balance and glucose homeostasis by microglia. However, the molecular mediators responsible for this phenotype remain unknown. We have now developed a diet-independent inducible model of microglial activation using the Designer Receptor Activated by Designer Drugs (DREADD) approach. Microglia expressing the Gq-coupled DREADD receptor hM3D are rapidly activated by CNO treatment with marked upregulation of TNFa expression. Nevertheless, the CNO treatment causes an immediate improvement in glucose tolerance even in HFD-fed mice. Unexpectedly, this effect can be blocked using icv pretreatment with either a specific TNF receptor antagonist or a melanocortin 3/4 receptor antagonist. While TNF signaling can disrupt leptin sensitivity in hypothalamic neurons, it also increases POMC neuron firing, promotes synaptic plasticity and activates the melanocortin pathway. Therefore, we hypothesize that HFD feeding acts through microglial TLR4 to triggers DIO susceptibility but improve glucose tolerance through the melanocortin pathway. To investigate these premises further, in Aim 1 we will determine whether astrocyte activation is dependent on microglial inflammatory signaling and required for microglia-induced DIO.
Aim2 will determine whether microglial TNF and melanocortin signaling are required for the improved glucose tolerance induced by microglial activation. Finally, Aim 3 investigates the peripheral mechanisms of improved glucose tolerance and includes a transcriptomic screen for additional microglial mediators of glucose homeostasis regulation. Together, these studies will help identify the cellular and molecular components of microglial activation that mediate its impact on obesity and diabetes pathogenesis.

Public Health Relevance

Obesity is a major global health problem because of its high prevalence and its resistance to medical therapies. Weight gain-promoting diets activate specialized central nervous system immune cells in brain centers that control appetite and metabolism, suggesting that these cells may be important targets for new treatments. This project investigates how the inflammatory signaling system used by these cells causes calorie overconsumption and weight gain but protects against diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK119754-03S1
Application #
10186848
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2018-09-12
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195