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Role of Hypothalamic MC4R in Glucose Homeostasis via a Novel Neuroendocrine Circuit involving the Kidneys and Adrenal Glands

Award Number: R01DK124619
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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We recently identified the contribution of hypothalamic MC4R in regulating blood glucose levels by influencing glycosuria through epinephrine and renal GLUT2. Moreover, we have demonstrated previously that diabetes decreases the hypothalamic Mc4r expression that consequently leads to defective counterregulatory response (CRR) to glucose deficits in mice. The molecular and integrative mechanisms underlying these clinically significant observations remain unknown. Specifically, how does hypothalamic MC4R regulates plasma epinephrine levels? Does a neural crosstalk between the hypothalamic MC4R and kidney GLUT2 coordinate the regulation of systemic glucose homeostasis via epinephrine? In our Preliminary Studies, we observed that MC4R restoration selectively in the corticotropin releasing hormone (CRH) neurons normalized plasma epinephrine levels in otherwise MC4R-deficient mice, indicating the role of MC4R- expressing CRH neurons in regulating plasma epinephrine levels. Unexpectedly, kidney-specific Glut2 knockout mice are protected from diabetes-mediated defective CRR to hypoglycemia and the mice show increased Mc4r and Crh mRNA levels in the hypothalamus, suggesting the influence of renal GLUT2 on the hypothalamic melanocortin system. Our Preliminary Data also indicate the contribution of renal, but not liver, gluconeogenesis toward restoration of normal blood glucose levels following hypoglycemia in the kidney-specific Glut2 knockout mice. Based on these preliminary findings, we hypothesize that hypothalamic MC4R-expressing CRH neurons are activated by the afferent renal nerves in response to glucose deficits to enhance plasma epinephrine, which in turn increases renal gluconeogenesis and restores blood glucose levels. Moreover, elevated kidney GLUT2 levels in diabetes compromises this activation of MC4R-expressing CRH neurons to impair counterregulatory response to hypoglycemia. We will test the hypotheses with the following Aims, Aim1: Determine the role of hypothalamic MC4R-expressing CRH neurons in integrating signals from renal afferent nerves to increase plasma epinephrine in response to hypoglycemia. Aim2: Identify the molecular and integrative (central versus peripheral) mechanisms – chronically elevated renal GLUT2, decreased renal afferent nerve activity, and/or blunted activation of hypothalamic MC4R-expressing CRH neurons - through which diabetes compromises the body’s ability to defend against hypoglycemia. Aim3: Establish the contribution of renal gluconeogenesis as a source of glucose to defend against hypoglycemia and identify the renal adrenergic receptors through which epinephrine increases glucose reabsorption and renal gluconeogenesis. Altogether, this project will likely identify a novel neuroendocrine circuit underlying the crosstalk between the hypothalamus, kidney and adrenal gland to coordinate systemic glucose homeostasis. This integrative circuit will probably inform the molecular basis of how diabetes compromises the body’s ability to increase plasma epinephrine in the face of glucose deficits leading to hypoglycemia-associated autonomic failure, a life- threatening condition in patients with type 1 or late-stage type 2 diabetes.


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	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	10/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$309,239
2025	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	10/22/2024	SUPPLEMENT FOR EXPANSION	-$147,075
2025	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/22/2024	NON-COMPETING CONTINUATION	-$162,163
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $323,136 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$323,136
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	9/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $323,136

Issue Date FY: 2023 ( Subtotal = $646,078 )
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/20/2023	NON-COMPETING CONTINUATION	$338,800
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/27/2023	SUPPLEMENT FOR EXPANSION	$307,278
														Subtotal = $646,078

Issue Date FY: 2022 ( Subtotal = $338,800 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/15/2022	NON-COMPETING CONTINUATION	$338,800
														Subtotal = $338,800

Issue Date FY: 2021 ( Subtotal = $338,800 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/20/2021	NEW	$338,800
														Subtotal = $338,800

Grand Total All Awards = $1,646,814

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Role of Hypothalamic MC4R in Glucose Homeostasis via a Novel Neuroendocrine Circuit involving the Kidneys and Adrenal Glands

Award Number: R01DK124619

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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