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Perilipin 5 in the Regulation of Adipose Tissue Function

Award Number: R01DK115875
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: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Perilipin 5 in the Regulation of Adipose Tissue Function - Project Abstract/Summary The rising prevalence of obesity and type 2 diabetes threatens to limit human healthspan by increasing the risks for cancer and cardiometabolic disease and to impose overwhelming economic burdens. New therapeutic strategies are urgently needed. Since the discovery of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled mitochondrial respiration. Advanced imaging in humans has revealed a favorable correlation between brown fat mass and cardiometabolic risk factors. A major gap in the field is a safe and effective pharmacological strategy to activate brown and/or beige adipocytes to promote negative energy balance, reverse obesity, and mitigate obesity-related metabolic disorders, such type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The overall goal of this application is to provide proof-of-concept for one such strategy that has been suggested by the lab’s long- standing research program on Perilipin 5 (PLIN5), a member of the Perilipin family of lipid droplet proteins that is expressed in oxidative tissues, including brown adipose tissue (BAT). A growing body of literature from our lab and others has implicated PLIN5 not only in the regulation of lipolysis at the lipid droplet surface, but also in the regulation of gene expression via interactions in the nucleus with SIRT1 and PGC1a and in the tethering of lipid droplets to mitochondria. Our published work in mice has shown that PLIN5 is required for the metabolic, transcriptional, and mitochondrial adaptations of BAT to cold stress. We have also shown that PLIN5 gain-of-function in BAT of mice can prevent glucose intolerance and fatty liver from high-fat diet and promote healthy remodeling of white adipose tissue (WAT) with prevention of adipocyte hypertrophy. In this renewal application we propose to test the hypothesis that promoting PLIN5 expression in BAT in conjunction with b3 adrenergic receptor agonist treatment of diet-induced obese mice will reverse adipocyte hypertrophy in WAT, reverse obesity, and reverse glucose intolerance. Aim 1 will elucidate the metabolic and signaling pathways responsible for the effects of PLIN5 on mitochondrial form and function in BAT and on systemic lipid and glucose metabolism by means of genetic mouse models, in vivo structure- function studies, and mechanistic mitochondrial experiments. Aim 2 will interrogate the signaling pathways and physiological responses associated with treatment of diet-induced obesity with a 2-hit intervention built on augmentation of PLIN5 in BAT in synergistic combination with b3 adrenergic receptor agonist treatment. Successful completion of these Aims may establish the conceptual foundation for a new therapeutic paradigm for treatment of obesity that is efficacious but at lower, non-toxic doses of existing medications.


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 = $541,200 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/23/2025	NON-COMPETING CONTINUATION	$541,200
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/18/2025	COMPETING CONTINUATION	$8
2025	2021	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/18/2025	NON-COMPETING CONTINUATION	-$8
														Subtotal = $541,200

Issue Date FY: 2024 ( Subtotal = $519,551 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/26/2024	NON-COMPETING CONTINUATION	$519,551
														Subtotal = $519,551

Issue Date FY: 2023 ( Subtotal = $541,200 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/24/2023	COMPETING CONTINUATION	$541,200
														Subtotal = $541,200

Issue Date FY: 2021 ( Subtotal = $405,000 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/27/2021	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2020 ( Subtotal = $405,000 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/16/2020	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2019 ( Subtotal = $405,000 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/23/2019	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2018 ( Subtotal = $405,000 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/3/2018	NEW	$405,000
														Subtotal = $405,000

Grand Total All Awards = $3,221,951

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Perilipin 5 in the Regulation of Adipose Tissue Function

Award Number: R01DK115875

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: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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