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.

Public Health Relevance

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). A related gap in knowledge is whether AT differences in MHO and MUO are also seen in the AT of healthy and unhealthy lean individuals, and in individuals prior to weight gain. We have documented the first spontaneous monkey model of MHO and unhealthy (MUO) obesity and will study visceral and subcutaneous AT cellular structure and mitochondrial function in lean and obese monkeys that differ by health status while cardiometabolic health is concurrently characterized. At study end we will have refined our knowledge of AT biology with clinically relevant imaging and measurable outcomes that will inform clinical assessment of obese people.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL142930-01A1
Application #
9683550
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Redmond, Nicole
Project Start
2018-12-15
Project End
2023-11-30
Budget Start
2018-12-15
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157