Item Details

abstract

Over 93 million Americans are obese, and 66 million suffer from metabolic syndrome (MetS). Obesity is defined by an accumulation of adipose tissue (AT). Although MetS correlates with obesity, 30% of obese individuals remain metabolically healthy (MHO; no MetS criteria aside from obesity), and ~15% of lean individuals still have MetS (MUL). The imperfect association of excess AT and MetS suggests that AT differs in healthy and unhealthy obese (MHO and MUO), and in healthy and unhealthy lean (MHL and MUL) individuals. AT depots differentially impact health, with subcutaneous (SQ) AT considered protective against metabolic abnormalities, while visceral (VIS) AT expansion generally increases inflammation. Our preliminary data in MHO/MUO and MHL/MUL nonhuman primates (NHPs) indicated that AT distribution does not differ by metabolic health status, leading us to hypothesize that AT dysfunction - not distribution - underpins metabolic defects. This dissertation aimed to define novel mediators of AT dysfunction by 1) determining SQ and VIS AT adipocyte and macrophage features that confer metabolic abnormalities, 2) disentangling the cell sources of SQ and VIS AT inflammatory markers, and 3) quantitating the in vivo effects of reducing pro-inflammatory senescent cells in AT. Aims 1 and 2 determined differences in adipocytes, macrophages, and inflammatory markers in the SQ and VIS AT of the four metabolic health groups through histological, immunohistochemical, transcriptomic, and protein analyses. Aim 3 defined the impacts of clearing AT senescent cells on these attributes. We utilized translationally relevant NHP models that demonstrate naturally occurring obesity and the range of metabolic abnormalities observed in people. We determined that healthiness corresponded with M2 macrophage-enriched distributions in both AT depots. Higher M2 macrophages were observed with greater SQ fatty acid oxidation gene expression in healthy obesity. Unhealthiness was characterized by lower M2 macrophages, immune activation, and a distinct Gram-negative enriched VIS AT microbiome. Additionally, we found that senolytic therapy combined with low-percentage caloric restriction improves glycemia and body composition, and reduces systemic inflammation. Together, these data identify new targets - namely M2 macrophages, the visceral microbiome, and senolytic drugs - that may mitigate health group-specific adipose tissue and systemic metabolic dysfunction.

subject

Adipose Tissue

Macrophages

Metabolic Syndrome

Nonhuman Primates

Obesity

Senolytics

contributor

Ruggiero, Alistaire (author)

Kavanagh, Kylie (committee chair)

Cox, Laura A. (committee member)

Parks, John S. (committee member)

Caudell, David L. (committee member)

Quinn, Matthew A. (committee member)

Key, Chia-Chi Chuang (committee member)

date

2022-09-17T08:35:50Z (accessioned)

2023-03-16T08:30:13Z (available)

2022 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2023-03-16 (terms)

identifier

http://hdl.handle.net/10339/101264 (uri)

language

en (iso)

publisher

Wake Forest University

title

Adipose Tissue Cellular Characteristics and Inflammation in Health- and Weight-Diverse Nonhuman Primates

type

Dissertation