Glucagon-like peptide 1 (GLP1) is a hormone that controls energy homeostasis, insulin release, and feeding behavior. GLP1 activates a complex neuroendocrine axis that coordinates systemic behavioral and metabolic responses to nutrient intake, with GLP1 receptor (GLP1R) expressed in many locations, including the vagus nerve, brainstem, and hypothalamus. The roles of some GLP1-responsive neurons remain poorly defined, in part due to a lack of appropriate genetic tools. Understanding the roles of different GLP1-responsive neurons is imperative, as therapeutic strategies that involve mimicry or stabilization of GLP1 provide clinically important methods for control of diabetes and potentially other metabolic disorders. GLP1R is expressed in a cohort of vagal sensory neurons, although the roles of vagal GLP1R neurons in feeding behavior, metabolism, and nausea are highly controversial. Recent studies indicate that vagal GLP1R is not required for the effects of GLP1R agonists on body weight or diabetes resolution, raising basic questions about (1) where vagal GLP1R neurons project in the body and brain, (2) what they detect, and (3) what physiological responses they evoke, all of which are unknown. In preliminary data, we used a molecular and genetic approach to deconstruct the sensory vagus nerve into cellular components. We generated a collection of 'ires-Cre' knock-in mice, including Glp1r-ires-Cre mice, and adapted powerful genetic techniques for connectivity mapping, in vivo imaging, and optogenetic control of neural activity in the vagus nerve. Using these approaches, we identified two subtypes of vagal afferents that innervate the lung, and exert powerful and opposing effects on breathing (Cell, 2015), and here, will use related techniques to study the sensory biology of vagal GLP1R neurons.
In Aim 1, we developed a strategy for introducing genetic tracers into vagal sensory neurons by adeno-associated virus infection, and will use this technique to map the projections of vagal GLP1R neurons in peripheral organs and the brainstem.
In Aim 2, we developed a novel in vivo imaging paradigm in vagal ganglia that involves a genetically encoded calcium indicator, and will use this technique to query the specific response properties of vagal GLP1R neurons.
In Aim 3, we will selectively activate or eliminate vagal GLP1R neurons using genetic approaches, and determine the impact on feeding behavior, metabolism, nausea, and other aspects of autonomic physiology. Together, these studies will provide needed information about the cell biology of vagal GLP1R neurons. Charting GLP1- responsive circuits at a cellular level will help reveal how GLP1 evokes diverse physiological responses in health and disease, and may provide an important foundation for future therapy development.

Public Health Relevance

Therapies based on glucagon-like peptide 1 (GLP1) provide an effective strategy for treatment of type 2 diabetes and potentially other metabolic disorders such as obesity. Additional studies are needed to understand various GLP1-responsive neural circuits as understanding these circuits could facilitate development of drugs with preferred specificity, efficacy, and route of administration. This project will use molecular and genetic approaches to study the sensory biology of vagal neurons containing GLP1 receptor, determining (1) their projections throughout the body and brain, (2) the sensory stimuli they detect, and (3) their functions in normal physiology and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103703-03
Application #
9392158
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Teff, Karen L
Project Start
2016-03-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Lou, Shan; Adam, Yoav; Weinstein, Eli N et al. (2016) Genetically Targeted All-Optical Electrophysiology with a Transgenic Cre-Dependent Optopatch Mouse. J Neurosci 36:11059-11073
Williams, Erika K; Chang, Rui B; Strochlic, David E et al. (2016) Sensory Neurons that Detect Stretch and Nutrients in the Digestive System. Cell 166:209-21