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Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

Award Number: R01DK097441
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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Uncoupling Protein 1 (UCP1) is a mitochondrial protein specific to thermogenic adipocytes (brown and beige fat) that uncouples cellular respiration and mitochondrial ATP synthesis to dissipate energy in the form of heat. Because UCP1 has been considered the sole thermogenic protein responsible for non-shivering thermogenesis in the adipose tissue, the prevailing dogma is that the action of UCP1 primarily mediates the functions of brown and beige fat, which promote the anti-obesity and anti-diabetic effects when activated. However, our data from the previous funding cycle and other labs suggest an incongruity in the metabolic phenotypes between brown/beige fat-deficiency and UCP1-deficiency: we found that beige fat-deficient mice, caused by the fat-specific deletion of PRDM16 or its co-factor EHMT1, develop obesity and glucose intolerance even under ambient temperature, whereas UCP1 knockout mice are not diabetic and develop obesity only under thermoneutrality. This discrepancy motivated us to search for UCP1-independent mechanisms in the regulation of energy homeostasis. We recently identified a non-canonical (UCP1-independent) thermogenic mechanism that may explain the above quandary. UCP1-independent thermogenesis involves ATP-dependent Ca2+ cycling through Sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b) and Ryanodine Receptor 2 (RyR2) in beige fat. Ca2+ cycling thermogenesis is activated, in part, through α1-AR signaling in response to a cold stimulus, and requires active glucose oxidation. Thereby beige fat functions as a “glucose sink” and improves systemic glucose tolerance. Notably, Ca2+ cycling thermogenesis is an evolutionally conserved mechanism in humans, mice, and also in pigs, a rare mammalian species that lacks a functional UCP1 protein. Accordingly, the current proposal aims to determine the biological significance and the mechanisms pertinent to this non-canonical thermogenesis in beige fat.


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 = -$13,237 )
2025	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	11/13/2024	NON-COMPETING CONTINUATION	-$13,237
														Subtotal = -$13,237

Issue Date FY: 2022 ( Subtotal = $495,593 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/28/2022	NON-COMPETING CONTINUATION	$495,593
														Subtotal = $495,593

Issue Date FY: 2021 ( Subtotal = $495,593 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	7/19/2021	NON-COMPETING CONTINUATION	$495,593
2021	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	11/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$75,559
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	11/9/2020	SUPPLEMENT FOR EXPANSION	-$75,559
														Subtotal = $495,593

Issue Date FY: 2020 ( Subtotal = $495,593 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	7/4/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$495,593
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	8	7/8/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $495,593

Issue Date FY: 2019 ( Subtotal = $615,030 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	7/16/2019	SUPPLEMENT FOR EXPANSION	$160,500
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/15/2019	NON-COMPETING CONTINUATION	$454,530
														Subtotal = $615,030

Issue Date FY: 2018 ( Subtotal = $453,114 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/4/2018	COMPETING CONTINUATION	$453,114
2018	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	9/20/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $453,114

Issue Date FY: 2017 ( Subtotal = $344,738 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	6/22/2017	NON-COMPETING CONTINUATION	$344,738
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/28/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $344,738

Issue Date FY: 2016 ( Subtotal = $344,738 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$344,738
														Subtotal = $344,738

Issue Date FY: 2015 ( Subtotal = $344,738 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/19/2015	NON-COMPETING CONTINUATION	$344,738
														Subtotal = $344,738

Issue Date FY: 2014 ( Subtotal = $345,127 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/5/2014	NON-COMPETING CONTINUATION	$343,650
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	9/6/2014	SUPPLEMENT FOR EXPANSION	$1,477
														Subtotal = $345,127

Issue Date FY: 2013 ( Subtotal = $329,524 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/26/2013	NON-COMPETING CONTINUATION	$329,524
														Subtotal = $329,524

Issue Date FY: 2012 ( Subtotal = $340,388 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/10/2012	NEW	$340,388
														Subtotal = $340,388

Grand Total All Awards = $4,590,939

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Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

Award Number: R01DK097441

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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