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Adipose Mitochondial Quality Control and Cardiovascular Function in Metabolically Healthy and Unhealthy Obese Monkeys

Award Number: R01HL142930
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Controversy exists regarding the metabolically healthy obese (MHO) classification, whether it is a transient state that precedes the development of cardiometabolic disease, or whether these individuals have preferred biological handling of excess adipose tissue (AT). We have documented the first spontaneous monkey model of MHO and unhealthy (MUO) obesity. Monkeys have near identical prevalence of MHO and MUO as well as healthy and healthy lean individuals (MHL/MUL) as humans, and are an excellent model of cardiovascular disease (CVD) and diabetes. Monkey MUO subcutaneous AT (SAT) has deficits in mitochondrial quality control and redistribution towards inflammatory M1-macrophages. We hypothesize that inadequate mitochondrial metabolism in SAT leads to greater ectopic fat accumulation and inflammation which drives the development of cardiometabolic diseases. It is unknown if these AT characteristics are observed in visceral adipose tissue (VAT) and if it is conserved across AT depots and over time. A related gap in knowledge is if AT in MUO shifts with weight loss towards improved mitochondrial function and a redistribution to include more anti-inflammatory M2-type macrophages, similar to that observed in the MHO state. We aim to answer questions pertaining to the generalizability of fat characteristics across AT depots in MHO/MHL and MUO/MUL, the stability of these phenotypes under caloric restriction, and persistence of these phenotypes in offspring that are genetically programmed for obesity. Our aims and outcomes are: 1. Characterize AT distribution and quality in lean and obese health-diverse monkeys. Surgical biopsies of SAT, VAT and liver will enable assessment of AT quality measures in MHO/MHL/MUO/MUL adult monkeys. We will quantitate mitochondrial bioenergetics, quality control and structure, inflammatory cell populations, gene expression profiles, cytokines, fibrosis, vascularity, fat density and distribution across sites in the body. Liver fat and histology will be additionally measured. Differences in AT quality will also be related to a novel outcome, peripheral blood mononuclear cell (PBMC) energetics; 2. Evaluate AT phenotypic stability and relate AT changes after weight loss to CVD risk and novel biomarkers. Repeated AT quality measures, PBMC bioenergetics before and after caloric restriction to achieve =10% weight loss will be performed. Changes will be related to changes in magnetic resonance imaging for CVD structure and function, biomarkers and MetS scores. 3. Document pre-obesity AT characteristics and biomarkers in at-risk youth. We will evaluate juvenile monkeys (2 and 3 year olds; puberty˜4 years) with the above-listed AT quality evaluations. Juveniles will be re- assessed as young adults for AT quality and health measures after weight gain. At completion we will have addressed gaps in knowledge about AT depots and health in a relevant animal model that is un-confounded by variable dietary and environmental influences. We aim to both identify causative and unique AT characteristics that will direct future research, and explore biomarkers that can be translated into clinical practice.


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 = $0 )
2024	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	5	3/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $668,735 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	5	11/14/2022	NON-COMPETING CONTINUATION	$601,862
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	002	5	3/6/2023	NON-COMPETING CONTINUATION	$66,873
2023	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	3	12/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $668,735

Issue Date FY: 2022 ( Subtotal = $666,352 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	4	12/16/2021	NON-COMPETING CONTINUATION	$599,717
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	4	6/18/2022	NON-COMPETING CONTINUATION	$66,635
														Subtotal = $666,352

Issue Date FY: 2021 ( Subtotal = $688,827 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$68,882
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	3	12/10/2020	NON-COMPETING CONTINUATION	$619,945
														Subtotal = $688,827

Issue Date FY: 2020 ( Subtotal = $689,686 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	001	2	3/7/2020	NON-COMPETING CONTINUATION	$34,484
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	2	11/22/2019	NON-COMPETING CONTINUATION	$655,202
														Subtotal = $689,686

Issue Date FY: 2019 ( Subtotal = $697,403 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cardiovascular Diseases Research	000	1	12/14/2018	NEW	$697,403
														Subtotal = $697,403

Grand Total All Awards = $3,411,003

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Adipose Mitochondial Quality Control and Cardiovascular Function in Metabolically Healthy and Unhealthy Obese Monkeys

Award Number: R01HL142930

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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