Microglia, the yolk sack-derived monocytes of the brain and spinal cord, plays a crucial role in immune responses, including inflammation. Recent work has expanded the role of microglia in the central nervous system (CNS), which includes phagocytosis of axon terminals and dendritic spines, thus pointing to an active role of microglia in neuronal circuit development and plasticity (Tremblay et al., 2011). Diet-induced obesity (DIO) induces microglia activation and hypothalamic inflammation as early as 3 days after high fat diet (HFD) exposure, before changes in body weight occur (Thaler et al., 2012). We in control also showed that activated microglia the hypothalamus act as a conductor of synaptic plasticity of the hypothalamic neurocircuitry involved in the of feeding behavior and glucose metabolism (Jin et al., 2016).Changes in microglial activity and function are processes that require dynamic changes in energy demand. During inflammation, changes in mitochondrial metabolism were suggested to contribute to microglia activation (Voloboueva et al., 2013; Gimeno-Bayon et al., 2014; Orihuela et al., 2016). Our preliminary data revealed that HFD-induced hypothalamic inflammation and microglia activation is paralleled by increased mitochondrial uncoupling protein 2 (UCP2) expression and a rapid (within 3 days) and transient (by day 7 days it is reversed) mitochondria fission event in microglia cells. We have previously shown that UCP2 propagates mitochondrial fission (Coppola et al., 2007; Andrews et al., 2008; Toda et al., 2016) via activation of dynamic-related peptide 1 (DRP1), a mitochondrial fission enabler (Toda et al., 2016). Corresponding with this, when we deleted UCP2 selectively from microglia in adult mice, HFD-exposure failed to trigger fission of mitochondria in hypothalamic microglia cells, and, it also diminished HFD-induced body weight gain and metabolic impairments of mice. Taken together these observations gave impetus to the central hypothesis of this proposal which is that DRP1 mediated mitochondrial fission via DRP1 activation in the early but not late phase of HFD feeding is indispensible for microglia activation, neuroinflammation, hypothalamic circuit adaptation to promote obesity. To test these hypotheses, we propose 3 Aims:
Specific Aim 1 will test the hypothesis that UCP2- induced mitochondrial fission mediated by DRP1 activation in the early phase (by day 3) of HFD feeding is critical for hypothalamic microglia activation, inflammation and obesity susceptibility.
Specific Aim 2 will test the hypothesis that HFD-induced microglia activation requires DRP1 for the rapid and transient mitochondria fission event in microglia cells in early but not late phase of HFD feeding to promote obesity.
Specific Aim 3 will determine whether activated microglia in HFD-fed DIO mice are upstream controllers of synaptic adaptations of arcuate POMC and AgRP neurons. The execution of these studies will deliver novel insights into central regulation of whole body glucose metabolism and offer novel avenues to combat diabetes by targeting brain mitochondrial dynamics.

Public Health Relevance

To understand the etiology of metabolic disorders, including obesity and type II diabetes, it is essential that we gain better insight into the mechanisms used by the central nervous system to regulate metabolism. The experiments proposed in this application will unmask the role of mitochondrial dynamics and UCP2 in microglia activation in the central regulation of energy homeostasis and will help us to better develop strategy for the treatment of metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK120321-01
Application #
9687196
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2018-09-20
Project End
2022-06-30
Budget Start
2018-09-20
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520