Adipocyte dedifferentiation in health and diseases

Abstract

Adipose tissues collectively as an endocrine organ and energy storage are crucial for systemic metabolic homeostasis. The major cell type in the adipose tissue, the adipocytes or fat cells, are remarkably plastic and can increase or decrease their size and number to adapt to changes in systemic or local metabolism. Changes in adipocyte size occur through hypertrophy or atrophy, and changes in cell numbers mainly involve de novo generation of new cells or death of existing cells. Recently, dedifferentiation, whereby a mature adipocyte is reverted to an undifferentiated progenitor-like status, has been reported as a mechanism underlying adipocyte plasticity. Dedifferentiation of mature adipocytes has been observed under both physiological and pathological conditions. This review covers several aspects of adipocyte dedifferentiation, its relevance to adipose tissue function, molecular pathways that drive dedifferentiation, and the potential of therapeutic targeting adipocyte dedifferentiation in human health and metabolic diseases.

Keywords: adipocyte; dedifferentiation; differentiation; metabolism; obesity.

Figure 1.. Differentiation and plasticity of adipocytes

During development, adipocytes originated from mesenchymal stem cells, which are then committed to adipogenic lineage (preadipocytes, also called adipogenic progenitor cells or adipogenic stem cells). Preadipocytes differentiate to become adipocytes, which have the plasticity to undergo hypertrophy (size increase), atrophy (size decrease), cell death, transdifferentiation (whitening and browning) and dedifferentiation in response to metabolic environments. Dedifferentiated cells can proliferate and re-differentiate to form adipocytes.

Figure 2.. Brown, beige and white adipocytes

Both human and mice have these three types of adipocytes. Brown adipocytes are mainly located in the interscapular BAT depot in rodents and humans (infant stage). They are more sparsely distributed along the vertebra in adult humans. Beige adipocytes are mainly located in subcutaneous WAT depots, intermingled with white adipocytes. White adipocytes are the predominant form of fat cells in humans and rodents where they are found under the skin (subcutaneous fat), in the bone marrow (marrow fat), in the muscle (intermuscular fat) and in the abdominal cavity (visceral fat). White and beige adipocytes are interconvertible: beige adipocytes can be converted from white adipocytes (a process called browning or beiging) in response to cold and other stimuli; or converted into white adipocytes (called whitening) in response to warm temperatures or a high-fat diet.

Figure 3.. Signaling regulation of adipocyte dedifferentiation in three models

(A) Activation of TGF-β1 drives dedifferentiation in the bleomycin-induced fibrosis model. (B) Canonical Wnt signaling driven by pancreatic cancer cell-derived Wnt3a has been implicated in the dedifferentiation of 3T3-L1 cells in a co-culture model. (C) Activation of Notch signaling drives dedifferentiation of white adipocytes in a mouse model that overexpresses Notch1 intracellular domain (NICD) specifically in adipocytes. Genes co-upregulated are shown in red arrows, down-regulated genes are shown in blue arrows. +: promoting; −: inhibiting.