Adipocyte Heterogeneity Underlying Adipose Tissue Functions

Abstract

Adipose tissue distribution in the human body is highly heterogeneous, and the relative mass of different depots is differentially associated with metabolic disease risk. Distinct functions of adipose depots are mediated by their content of specialized adipocyte subtypes, best exemplified by thermogenic adipocytes found in specific depots. Single-cell transcriptome profiling has been used to define the cellular composition of many tissues and organs, but the large size, buoyancy, and fragility of adipocytes have rendered it challenging to apply these techniques to understand the full complexity of adipocyte subtypes in different depots. Discussed here are strategies that have been recently developed for investigating adipocyte heterogeneity, including single-cell RNA-sequencing profiling of the stromal vascular fraction to identify diverse adipocyte progenitors, and single-nuclei profiling to characterize mature adipocytes. These efforts are yielding a more complete characterization of adipocyte subtypes in different depots, insights into the mechanisms of their development, and perturbations associated with different physiological states such as obesity. A better understanding of the adipocyte subtypes that compose different depots will help explain metabolic disease phenotypes associated with adipose tissue distribution and suggest new strategies for improving metabolic health.

Figure 1.

Heterogeneous adipose tissue distribution contributes to diversity in body shape. Individuals with identical BMI may have drastically different body shapes because of different adipose depot volumes in different parts of the body. In the extremes, “apple-shaped” individuals have adipose tissue concentrated in the abdomen (second left) and “pear-shaped” individuals have relatively high gluteal and femoral adipose tissue volume (left most). In other cases, individuals may have relatively even adipose distribution.

Figure 2.

Morphological features of brown, beige, and white adipocytes in adipose tissues. White adipocytes in white adipose tissue, exemplified by mouse gonadal fat (left) are larger and contain a single lipid droplet per cell. Brown adipocytes in mouse interscapular brown adipose tissue (right), are smaller in size and contain numerous lipid droplets. Beige adipocytes in inguinal fat of cold-exposed mice (middle), are intermediate in size and have characteristics of both white and brown adipocytes, having a large droplet and multiple small droplets in the same cell, or multiple small droplets. Bottom row displays a higher magnification image of each tissue type. Scale bar: 50 μm (top row); 25 μm (bottom row).

Figure 3.

Multiple single-cell profiling approaches in assessing adipocyte heterogeneity. Because adipocytes in adipose tissue are difficult to isolate, different approaches have been used for assessing adipocyte heterogeneity at the single-cell level. Collagenase digestion separates adipose tissue into a floating cell layer and a stromal vascular fraction (SVF), which pellets after centrifugation. Cells in SVF are amenable to cell sorting and single-cell profiling, as exemplified in previous work [13-17]. The single-nuclei profiling approach has been applied to the collagenase-digested floating cell layer [18], as well as directly on adipose tissue [19, 20]. As an alternative to direct profiling of primary adipocytes, clonally expanded adipose tissue-derived progenitor cells were profiled before and after differentiation and thermogenic induction [21].

Figure 4.

Model of adipose development based on single-cell transcriptomics. New adipocytes are developed from multipotent mesenchymal progenitors. Once committed to adipocyte fate, cells accumulate lipid droplets and expand in size. Mature white adipocytes contain single large lipid droplet (unilocular), whereas developing adipocytes and beige adipocytes have multiple smaller lipid droplets per cell (multilocular). Gene signatures of adipocytes in different developmental states are identified from single-cell RNA-sequencing of the progenitors and single nuclei RNA-sequencing of the mature adipocytes. The developmental stages of the reported adipocyte subtypes are inferred based on knowledge of adipocyte development. The full trajectory and the determinants for cell states or fate transitions remain to be identified.