Wednesday, July 30, 2025 7/30/2025

White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin

Award Number: R01DK099110
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: 07/05/2013
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin - White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin Metabolic dysregulation with all of it pathophysiological sequelae, including diabetes, cardiovascular disease and cancer, continues to be on the rise. We need to identify new areas that can be targeted for improvements in systemic metabolism. Over the last funding period, we have made significant progress towards defining key processes in the white adipocyte that lead to mitochondrial challenges and consequently, impaired adipose tissue function. These include challenges to the mitochondrial import machinery through overexpression of Amyloid Precursor Protein , loss of mitochondrial DNA and a dysregulation in iron metabolism through overexpression of mitoNEET and mitoferritin. We have applied many of these challenges to other cell types of relevance in adipose tissue, such as macrophages and adipocyte precursor cells. Here, we propose to integrate these challenges and observe how they feed into the Integrated Stress Response of mitochondria. We will analyze how endoplasmic reticulum (ER) stress and the mitochondrial stress pathways result in altered cellular physiology of the white adipocyte. We can carefully time and titrate these mitochondrial manipulations, then probe them either in the presence or absence of the integral mitochondrial stress sensor, DELE1. We will examine these phenomena in the following areas: A) at the cellular level in the mature adipocyte; B) in the microenvironment at the level of whole adipose tissue physiology; C) at the whole-body level, assessing the systemic effects of the Integrated Stress Response. Specifically, we propose to address the underlying mechanisms with the following hierarchical approaches: In Aim 1, we will measure and manipulate mitochondrial stress. In Aim 2, we will manipulate mitochondrial matrix iron levels and assess the impact on the Integrated Stress Response. In Aim 3, we will address the interplay between the mitochondrial and ER stress phenomena. In Aim 4, we will determine the role that the Integrated Stress Response has in activating the removal and packaging of sub-mitochondrial particles through exosomes. Combined, this proposal will provide significant novel insights into the downstream consequences of mitochondrial dysfunction, ER stress and the Integrated Stress Response in the white adipocyte in vivo. We are uniquely positioned to address these aims with mouse models that we have generated and characterized during the initial ten years of this grant. In adipocytes, these interventions will severely tip the balance of lipid storage, lipid oxidation and carbohydrate metabolism, thereby contributing directly to the development of obesity and insulin resistance. These experiments will also enable us to carefully dissect the effects of altered mitochondrial function on the production of the critical adipokine, adiponectin. These are the first comprehensive in vivo experiments assessing the role of the Integrated Stress Response in the white adipocyte. As such, this will enhance our understanding of how we define a properly functioning adipocyte.


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 = $624,266 )
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	001	12	6/12/2025	NON-COMPETING CONTINUATION	$62,426
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	000	12	2/14/2025	NON-COMPETING CONTINUATION	$561,840
														Subtotal = $624,266

Issue Date FY: 2024 ( Subtotal = $624,266 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	3/22/2024	COMPETING CONTINUATION	$624,266
2024	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	12/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $624,266

Issue Date FY: 2022 ( Subtotal = $497,340 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/22/2022	NON-COMPETING CONTINUATION	$497,340
														Subtotal = $497,340

Issue Date FY: 2021 ( Subtotal = $497,340 )
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	9	4/20/2021	NON-COMPETING CONTINUATION	$497,340
														Subtotal = $497,340

Issue Date FY: 2020 ( Subtotal = $497,340 )
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	8	4/15/2020	NON-COMPETING CONTINUATION	$497,340
														Subtotal = $497,340

Issue Date FY: 2019 ( Subtotal = $497,340 )
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	7	4/23/2019	NON-COMPETING CONTINUATION	$497,340
														Subtotal = $497,340

Issue Date FY: 2018 ( Subtotal = $497,340 )
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	6	3/26/2018	COMPETING CONTINUATION	$497,340
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	002	6	7/30/2018	COMPETING CONTINUATION	$8,002
2018	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/30/2018	NON-COMPETING CONTINUATION	-$8,002
														Subtotal = $497,340

Issue Date FY: 2017 ( Subtotal = $464,280 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/12/2017	NON-COMPETING CONTINUATION	$417,852
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/15/2017	NON-COMPETING CONTINUATION	$46,428
														Subtotal = $464,280

Issue Date FY: 2016 ( Subtotal = $464,280 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/4/2016	EXTENSION WITH OR WITHOUT FUNDS	$464,280
														Subtotal = $464,280

Issue Date FY: 2015 ( Subtotal = $464,280 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/30/2015	NON-COMPETING CONTINUATION	$464,280
														Subtotal = $464,280

Issue Date FY: 2014 ( Subtotal = $464,280 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/9/2014	NON-COMPETING CONTINUATION	$464,280
														Subtotal = $464,280

Issue Date FY: 2013 ( Subtotal = $464,280 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/4/2013	NEW	$464,280
														Subtotal = $464,280

Grand Total All Awards = $6,056,632

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White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin

Award Number: R01DK099110

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: 07/05/2013

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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