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Discovering new brain-based treatments for obesity and diabetes

Research

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.

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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.  MicrogliaConversely, 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 synapticCapillary 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.

Publications

Click here for a full list of publications

News

Atypical PKC paper published in Diabetes

UW Diabetes Institute Researchers Published in Nature Communications

Astrocyte inflammation and obesity paper accepted at Molecular Metabolism

UW Diabetes Institute Researcher Mauricio Dorfman, PhD, Receives AHA Scientist Development Grant

DOCE Researcher Joshua Thaler, MD, PhD, Receives ADA Pathway Award

DOCE Researcher Joshua Thaler, MD, PhD, Receives NIH R03

DOCE Researcher Joshua Thaler, MD, PhD, Receives UW Royalty Research Award

DOCE Researcher Joshua Thaler, MD, PhD, Receives 2013 Fialkow Award

DOCE Researcher Joshua Thaler, MD, PhD, Receives Early Investigator Award

 

Lab Life

Summer Opening-the-lab BBQ party June 2015 with families

Summer Opening-the-lab BBQ party June 2015 with families

Mauricio's Birthday April 2016

Mauricio’s Birthday April 2016

  • Members of the Laboratory

     Thaler Joshua Thaler, MD, PhD
     Dorfman photo Mauricio Dorfman, PhD
    Research Assistant Professor
     Douglass John Douglass, PhD
    Senior Fellow
     Fasnacht Rachael Fasnacht, MS
    Research Scientist
     Lara Lince Fernando Lara Lince, MD
    Laboratory Volunteer
    Li Jenny Li, PhD
    Visiting Scientist
  • Contact Us

    Address:
    UW Diabetes Institute
    University of Washington School of Medicine
    South Lake Union Campus
    850 Republican Street Rm S240
    Seattle, WA 98109-8055

    Phone/Fax:
    Fax: (206) 897-5293
    Josh Thaler: (206) 897-1802
    Laboratory Main Line: (206) 616-2482

    Email Addresses:
    Joshua Thaler: jpthaler@uw.edu
    Mauricio Dorfman: dorfmanm@uw.edu
    John Douglass: jddoug@uw.edu
    Rachael Fasnacht: fasnacht@uw.edu
    Fernando Lara Lince: flara@uw.edu
    Jenny Li: jennyli@uw.edu

     

    Careers

    To inquire about Postdoctoral and Graduate Student Openings click on: jpthaler@uw.edu