Contribution of adipogenesis to healthy adipose tissue expansion in obesity

Abstract

The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance. Healthy WAT expansion, observed in the "metabolically healthy" obese, is generally associated with the presence of smaller and more numerous adipocytes, along with lower degrees of inflammation and fibrosis. Here, we highlight recent human and rodent studies that support the notion that the ability to recruit new fat cells through adipogenesis is a critical determinant of healthy adipose tissue distribution and remodeling in obesity. Furthermore, we discuss recent advances in our understanding of the identity of tissue-resident progenitor populations in WAT made possible through single-cell RNA sequencing analysis. A better understanding of adipose stem cell biology and adipogenesis may lead to novel strategies to uncouple obesity from metabolic disease.

Figure 1. Inadequate energy storage in adipose tissue underlies insulin resistance.

Left: Lipodystrophy is characterized by an absolute or partial adipocyte deficiency, triggered by impaired adipocyte differentiation or triglyceride synthesis. This leads to ectopic lipid accumulation in other tissues, including the liver, skeletal muscle, heart, and pancreas. Toxic accumulation of lipid intermediates within these tissues leads to the development of insulin resistance. Middle: Pathologic obesity is often characterized by a relative adipocyte deficiency: limited expandability of the subcutaneous fat tissue, preferential expansion of visceral adipose tissue depots, and unhealthy adipose tissue remodeling (inflammation, fibrosis, limited adipogenesis). This is associated with ectopic lipid accumulation and insulin resistance, similar to what is observed in the lipodystrophy. Right: Metabolically healthy obesity is characterized by adequate expansion of protective subcutaneous depots, healthy adipose tissue remodeling (adipocyte hyperplasia), and limited ectopic lipid deposition.

Figure 2. New strategies to isolate adipose tissue–resident progenitor subpopulations from murine gonadal adipose tissue.

(A) Gonadal WAT depots of adult mice harbor functionally distinct PDGFRβ⁺ subpopulations. Molecular markers, including cell surface markers, are shown. The PDGFRβ⁺LY6C^–CD9^– fraction represents highly adipogenic adipocyte precursor cells (APCs) enriched in the expression of Pparg. These cells differentiate spontaneously upon reaching confluence in vitro when maintained in media containing insulin. The PDGFRβ⁺LY6C⁺ fraction represents fibro-inflammatory progenitors (FIPs). These cells are largely refractory to adipogenic stimuli and can actually be anti-adipogenic. (B) FACS strategy to isolate PDGFRβ⁺ subpopulations from perigonadal WAT of adult mice. Following the depletion of endothelial (CD31⁺) and hematopoietic cells (CD45⁺) from the stromal vascular fraction of digested adipose tissue, PDGFRβ⁺ cells can be subdivided into APCs and FIPs on the basis of LY6C and CD9 expression.

Figure 3. New strategies to isolate adipose tissue–resident progenitor subpopulations from murine inguinal adipose tissue.

(A) Merrick et al. (80) and Schwalie et al. (81) identify functionally distinct subpopulations of adipose precursors in inguinal WAT of adult mice. Molecular markers, including cell surface markers, are shown. Using the nomenclature from Merrick et al., interstitial progenitor cells (IPCs) represent multipotent cells that can give rise to more committed, highly adipogenic, ICAM1⁺ preadipocytes, along with a previously unrecognized CD142⁺ adipocyte precursor population. (B) FACS strategy to isolate functionally distinct adipogenic and anti-adipogenic subpopulations from inguinal WAT of adult mice. CD142^–DPP4⁺ IPCs represent a primitive stem cell population. CD142^–ICAM1⁺ cells represent committed preadipocytes. Importantly, these two populations can be identified in human subcutaneous adipose tissue using the same markers, and appear similar to the SCA-1⁺CD55⁺ and SCA-1⁺VAP1⁺ populations identified by Schwalie et al. Merrick et al. identified an additional preadipocyte population that is among the CD142⁺ cells (termed group 3 cells). IPCs give rise to ICAM1⁺ and CD142⁺ preadipocytes. Anti-adipogenic Aregs can be isolated on the basis of CD142 and ABCG1 expression (CD142⁺ABCG1⁺).