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The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis

Award Number: R21DK121266
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2019
PERIOD OF PERFORMANCE END DATE: 04/14/2023

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The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis - The current obesity epidemic warrants improved strategies for preventing and treating this increasingly devastating disease. Recently, our collaborative group examined the obesity-prone Samoan population and identified a missense variant in a putative transcriptional regulator (CREBRFR457Q) that increases BMI and adiposity. Little is understood about CREBRF and even less for the mechanisms by which its obesity-risk variant influence these phenotypes in humans. Because food intake, energy expenditure, and fat storage are orchestrated between the periphery and the brain, we examined in murine models that CREBRF was expressed and enriched in the hypothalamus throughout embryonic development and in adulthood is regulated during feeding state in a cell-specific manner. Therefore, the overall objective of this proposal is to understand how CREBRF and its obesity-risk variant contribute to the central regulation of energy homeostasis and, more specifically, to the development and function of POMC and AgRP neurons in the arcuate nucleus of the hypothalamus during nutritional stress in a sex-specific manner. Our central hypothesis is that CREBRF and its obesity-risk variant influence proliferation, differentiation, and subsequent activation/output of key hypothalamic neurons that control food intake, energy expenditure, and body weight. This hypothesis is supported by the following preliminary data: 1) humans expressing the CREBRFR457Q variant have increased BMI and adiposity, 2) mice lacking CREBRF have reduced body weight and food intake, 3) wild type CREBRF is reciprocally regulated in POMC and AgRP neurons in response to fasting, and 4) CREBRF is expressed in the embryonic hypothalamus and induced corresponding with neurogenesis. The central hypothesis will be tested using available cell and mouse models to achieve the following two specific aims: 1) to determine the impact of CREBRF and its obesity-risk variant on embryonic hypothalamic development, and 2) to determine the impact of CREBRF and its obesity-risk variant on gene expression in key adult hypothalamic neurons that regulate energy balance during various feeding states. This research is innovative because it uses a multidisciplinary approach and state-of-the-art techniques to elucidate mechanisms by which a novel human obesity-risk variant in a poorly understood gene influences the central regulation of energy homeostasis. This research is significant because it is directly relevant to populations with a high prevalence of the risk allele and because it is likely to reveal novel insights into the general regulation of energy homeostasis and pathogenesis of more common obesity in humans. These findings are expected to have broad translational impact because they will provide fundamental understanding for a relatively unknown gene and reveal novel mechanisms that can be targeted for prevention and/or treatment of obesity in a sex-specific manner. Additionally, this NIDDK R21 will support the generation of high-impact publications and preliminary data for subsequent R01 proposals further examining the role of CREBRF on hypothalamic development, in energy homeostasis, and other disease-relevant processes.


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: 2024 ( Subtotal = -$90,001 )
2024	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/20/2023	NON-COMPETING CONTINUATION	-$90,001
														Subtotal = -$90,001

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $195,625 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/26/2021	NON-COMPETING CONTINUATION	$195,625
														Subtotal = $195,625

Issue Date FY: 2020 ( Subtotal = $195,625 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$195,625
														Subtotal = $195,625

Issue Date FY: 2019 ( Subtotal = $195,625 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2019	NEW	$195,625
														Subtotal = $195,625

Grand Total All Awards = $496,874

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The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis

Award Number: R21DK121266

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2019

PERIOD OF PERFORMANCE END DATE: 04/14/2023

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