Abstract
Obesity is a serious health concern and is associated with a reduced quality of life and a number of chronic diseases, including diabetes, heart disease, stroke, and cancer. With obesity rates on the rise worldwide, adipose tissue biology has become a top biomedical research priority. Despite steady growth in obesity-related research, more investigation into the basic biology of adipose tissue is needed to drive innovative solutions aiming to curtail the obesity epidemic. Adipose progenitor cells (APCs) play a central role in adipose tissue homeostasis and coordinate adipose tissue expansion and remodeling. Although APCs are well studied, defining and characterizing APC subsets remains ambiguous because of ill-defined cellular heterogeneity within this cellular compartment. In this study, we used single-cell RNA sequencing to create a cellular atlas of APC heterogeneity in mouse visceral adipose tissue. Our analysis identified two distinct populations of adipose tissue-derived stem cells (ASCs) and three distinct populations of preadipocytes (PAs). We identified novel cell surface markers that, when used in combination with traditional ASC and preadipocyte markers, could discriminate between these APC subpopulations by flow cytometry. Prospective isolation and molecular characterization of these APC subpopulations confirmed single-cell RNA sequencing gene expression signatures, and ex vivo culture revealed differential expansion/differentiation capabilities. Obese visceral adipose tissue featured relative expansion of less mature ASC and PA subpopulations, and expression analyses revealed major obesity-associated signaling alterations within each APC subpopulation. Taken together, our study highlights cellular and transcriptional heterogeneity within the APC pool, provides new tools to prospectively isolate and study these novel subpopulations, and underscores the importance of considering APC diversity when studying the etiology of obesity.
Highlights
Mammalian adipose tissue is generally divided into two types: white adipose tissue (WAT) and brown adipose tissue
Substantial heterogeneity exists within these two general subtypes; WAT, for example, can be subdivided into subcutaneous (SWAT) and visceral (VWAT) depots, and cells within these depots can vary depending on precise anatomical locations
We modeled diet-induced obesity (DIO) using a shortterm, high-fat dietary formulation that featured elevated fat (40–45% kcal) and sucrose (36.8% by weight) content
Summary
Mammalian adipose tissue is generally divided into two types: white adipose tissue (WAT) and brown adipose tissue. Substantial heterogeneity exists within these two general subtypes; WAT, for example, can be subdivided into subcutaneous (SWAT) and visceral (VWAT) depots, and cells within these depots can vary depending on precise anatomical locations. WAT is capable of remarkable expansion, a property that left unchecked results in excess adipose tissue accumulation, obesity, and related pathologies. The two main forces that underlie WAT expansion are adipocyte hyperplasia and adipocyte hypertrophy. The latter involves increases in adipocyte size/volume, largely fueled by shifts in the balance between lipid storage (lipogenesis) and lipid breakdown (lipolysis). Adipocyte hyperplasia involves an increase in adipocyte number, a result of aberrant adipose progenitor cell (APC) expansion, differentiation, and self-renewal programs. Understanding fundamental APC properties is highly relevant as obesity-related research moves forward
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