Deciphering adipose tissue heterogeneity

Abstract

Obesity is an excess accumulation of adipose tissue mass, and, together with its sequelae, in particular type II diabetes and metabolic syndrome, obesity presents a major health crisis. Although obesity is simply caused by increased adipose mass, the heterogeneity of adipose tissue in humans means that the response to increased energy balance is highly complex. Individual subjects with similar phenotypes may respond very differently to the same treatments; therefore, obesity may benefit from a personalized precision medicine approach. The variability in the development of obesity is indeed driven by differences in sex, genetics, and environment, but also by the various types of adipose tissue as well as the different cell types that compose it. By describing the distinct cell populations that reside in different fat depots, we can interpret the complex effect of these various players in the maintenance of whole-body energy homeostasis. To further understand adipose tissue, adipogenic differentiation and the transcriptional program of lipid accumulation must be investigated. As the cell- and depot-specific functions are described, they can be placed in the context of energy excess to understand how the heterogeneity of adipose tissue shapes individual metabolic status and condition.

Keywords: adipocyte; adipose tissue; cellular heterogeneity; preadipocyte.

Figure 1

The heterogeneity of adipose tissue has different drivers. The genetic background of different individuals can synergize with differences in cellular heterogeneity as well as variation in adipose tissue depot size and function. A person’s adipose tissue would then drive a distinct metabolic response to physiologic stimuli, such as diet, but also to therapeutic intervention (Px). This may require a personalized medicine approach to treat metabolic disease and indeed instruct decisions in the diet.

Figure 2

Cellular heterogeneity of adipose tissue. Different cell types interact in adipose tissue to maintain homeostasis. To generate and maintain a pool of mature adipocytes, different precursor populations (depicted as slightly different shades with different color nuclei) are maintained in a stem cell niche, where they can react to different cues that regulate their adipogenic differentiation. The stem cell niche is located in close proximity to the vasculature, where it can respond to endocrine signals that can also modulate the function of mature adipocytes. Cells from the immune system are critical for tissue remodeling and also regulate the inflammatory milieu of adipose tissue response to energy balance in a process called metabo-inflammation. Finally, different kinds of mature adipocytes arise from the distinct progenitor cell pools and can be acutely activated by neurons to control thermogenesis and lipolysis.

Figure 3

Characteristics of white and brown adipose tissue. Abundant mitochondria and a high level of vascularization make brown adipose tissue distinct from white adipose tissue in vivo; however, in vitro–differentiated adipocytes from brown and white precursors are morphologically indistinguishable. In vivo, white adipose tissue stores lipid in a unilocular fat droplet, whereas, in vitro, white adipocytes share a multilocular morphology with brown adipose tissue in vivo and in vitro. On a molecular level, the genes that mark cells from these two different depots are different both at the preadipocyte stage and in mature adipocytes. Human white preadipocytes express high levels of SSTR1, PTPRB, FAT1, and ACTC1 and after differentiation can be discriminated from brown adipocytes by increased expression of ASC-1 and leptin, which allow them to perform their primary function of energy storage. Human brown preadipocytes, on the other hand, express PREX1, CTTNBP2, DMRTA1, and EDNRB. Differentiation leads to expression of UCP1, which facilitates energy expenditure, and human brown adipocytes can be further discriminated from white adipocytes by expression of P2RX5, KCNK3, and MTUS1.

Figure 4

Energy balance drives changes in BAT and WAT that can activate preadipocyte differentiation. In BAT, increased thermogenic demand activates energy expenditure by catabolizing fuel, and a long-term imbalance can stimulate differentiation of new brown adipocytes and increased tissue size. Excess energy can be stored in BAT and is usually characterized by a decrease in number and increase in size of lipid droplets, as well as decreased expression of UCP1. In some mouse models, such as chronic high fat–diet feeding, BAT adipocytes can even appear unilocular, although it is unclear if these cells are truly white adipocytes or if this unilocular lipid droplet is a further adaptation of brown adipocytes to energy excess. WAT participates in energy expenditure during thermogenesis, first as a fuel source that can release stored fuel to thermogenic BAT, but, during chronic cold exposure, these lipolysis products are also able to recruit macrophages that secrete molecules, such as OPN, to stimulate differentiation of UCP1⁺ beige/brite adipocytes in situ. Energy excess causes expansion of WAT, first by hypertrophy of adipocytes but then, through a process similarly associated with macrophage recruitment, through the differentiation of adipocytes into new mature adipocytes. Hypertrophy and hyperplasia occur at different rates in different adipose tissue depots.