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Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis

Award Number: R01DK125081
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Obesity has become a world-wide epidemic problem, and is an independent risk factor for a panel of metabolic diseases, including insulin resistance/type 2 diabetes, dyslipidemia, cardiovascular diseases, and cancer. The stomach-derived orexigenic hormone ghrelin acting through its receptor growth hormone secretagogue receptor 1a (GHSR) is a key mediator of energy homeostasis. GHSR is widely expressed in the brain and on gastrointestinal vagal sensory neurons. In the current proposal, we discovered that in addition to the well characterized vagal GHSRs, gastrointestinal sensory neurons emanating from spinal dorsal root ganglia (DRG) robustly express GHSRs. In addition, DRG GHSR-containing neurons innervates the gastrointestinal tract, and DRG GHSR is markedly induced by energetic challenges, including food deprivation and cold exposure, suggesting DRG ghrelin/GHSR signaling is important in regulating energy homeostasis. Interestingly, sensory GHSR deletion protects against diet-induced obesity primarily due to increased energy expenditure via increased adipose tissue sympathetic outflow and thermogenesis. Thus, we have identified a novel pathway in which gut non-vagal sensory GHSR neurons negatively regulate energy homeostasis via suppression of adipose tissue sympathetic outflow, thermogenesis and whole body energy expenditure. The overall goal of this project is to test the importance of ghrelin/GHSR signaling on peripheral sensory neurons in regulating whole body metabolic homeostasis, and to investigate the neuronal mechanisms by which sensory GHSR regulates adipose tissue sympathetic outflow. In Specific Aim 1, the importance of sensory GHSR in regulating energy homeostasis will be tested using DRG sensory neuron-specific deletion or re-activation of GHSR. In Specific Aim 2, the neuronal circuitry connecting gut sensory GHSR signaling to adipose tissue sympathetic outflow will be investigated via viral tract tracer mapping. In addition, the possible involvement of central melanocortin signaling pathways as a downstream target connecting sensory GHSR signaling to adipose tissue sympathetic outflow will be tested. Completing this project will greatly expand our current knowledge of the neuroendocrine regulation of energy homeostasis, and will provide novel therapeutic targets in the preventing and treatment of obesity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $643,369 )
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	1/31/2023	SUPPLEMENT FOR EXPANSION	$126,165
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/30/2023	NON-COMPETING CONTINUATION	$517,204
														Subtotal = $643,369

Issue Date FY: 2022 ( Subtotal = $601,313 )
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/29/2022	NON-COMPETING CONTINUATION	$51,721
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/25/2022	NON-COMPETING CONTINUATION	$465,483
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/27/2022	SUPPLEMENT FOR EXPANSION	$84,109
														Subtotal = $601,313

Issue Date FY: 2021 ( Subtotal = $518,429 )
2021	2021	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/4/2021	NON-COMPETING CONTINUATION	$518,429
														Subtotal = $518,429

Issue Date FY: 2020 ( Subtotal = $549,700 )
2020	2020	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/9/2020	NEW	$549,700
														Subtotal = $549,700

Grand Total All Awards = $2,312,811

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Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis

Award Number: R01DK125081

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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