Trends in Cell Biology
ReviewMicroenvironmental Control of Adipocyte Fate and Function
Section snippets
Adipose Depots and Functions
Adipose tissue is distributed over multiple subcutaneous and visceral depots, typically accounting for 15–30% of total human body weight [1]. Although plasticity between canonical phenotypes is observed 2, 3, adipose tissue is generally considered either ‘white’, characterized by adipocytes with a single lipid droplet for efficient energy storage, or ‘brown’, characterized by adipocytes with multiple lipid droplets, numerous enlarged mitochondria expressing UCP1 for uncoupled oxidative
The Developing Adipocyte Niche
Lineage-tracing experiments in animals indicate that different adipose depots, and sometimes even different adipocytes within the same depot, arise from a variety of mesenchymal precursors of neural crest or mesodermal origin 18, 19, 20. Brown adipocytes are derived from progenitors expressing Myogenic Factor 5 that also have the potential to form skeletal muscle [21]. The complete set of white adipose precursors has not been fully characterized, but includes multipotent mural cells expressing
Adipocyte Interactions with the Extracellular Matrix
Typical of the loose areolar connective tissue in which it develops, adipose is supported by an isotropic matrix of collagen and elastic fibers. Extracellular fibronectin and laminin form networks with collagen fibers [29] and provide attachment points for integrins anchored in the adipocyte membrane [30] (Figure 2). Integrins are heterodimers with alpha and beta subunits, the combination of which dictates ligand specificity [31]. Similar to receptors for paracrine signals, integrins transduce
Adipose Cytoarchitecture and Adipocyte–Adipocyte Interactions
Accompanying changes to the extracellular matrix, the cytoskeleton is also remodeled as spherical adipocytes form from stellate progenitors 46, 47. Decreased RhoA activity at the onset of adipogenesis triggers the disassembly of actin stress fibers, freeing globular actin to sequester the antiadipogenic transcriptional co-activator Megakaryoblastic Leukemia-1 [48]. To accommodate expanding lipid droplets, vimentin transcription increases to proportionally expand the vimentin cage surrounding
Mechanotransduction in Adipocytes
The expansion of lipid droplets and cytoskeletal rearrangements in adipogenesis alter the mechanical properties of the tissue. For example, cell stiffness, the resistance of an object to deformation by an applied force, was measured during in vitro differentiation of mouse 3T3-L1 preadipocytes. Stiffness increased from 300–900 Pa in preadipocytes to ∼2 kPa in white adipocytes, attributable to the fact that lipid droplets are stiffer than the surrounding cytoplasm and occupy an increasing majority
Heterotypic Cell Interactions Within Adipose Depots
Adipocytes share their microenvironment with multiple cell types that interact to coordinate adipose functions. A few examples are given below to demonstrate the role and prevalence of heterotypic cell interactions in adipose depots, but more comprehensive reviews exist that expand upon adipose vasculature [78], neurons [79], and leukocytes [80], among other cell types 81, 82. In addition to the previously mentioned inductive role during adipose depot development (see ‘The Developing Adipocyte
Adipocyte Microenvironments in Disease
Given the regulatory roles for the microenvironment in normal adipose development and function, it is no surprise that altered adipose microenvironments are associated with disease. While the classification of obesity in and of itself as a disease is debated [94], there is significant risk for cardiovascular and other diseases with obesity [95] that may be explained by changes to the adipose microenvironment during tissue expansion. As discussed previously, adipose tissue expansion requires
Applying Regulatory Principles of Adipocyte Microenvironments
How are these principles of microenvironmental control of adipocyte function being applied? Currently, in vitro adipocyte (and most cell) culture is performed on generic 2D polystyrene that lacks the regulatory features of the in vivo microenvironment. In an effort to improve the physiological relevance of in vitro studies, cell culture technologies are in development to mimic the microenvironments of multiple organs, including heart [111], skeletal muscle [112], eye [113], lung [114], kidney
Concluding Remarks
In summary, our growing appreciation for the adipocyte microenvironment in adipose development and function provides motivation for the comprehensive characterization of the adipocyte microenvironment as well as experiments to determine the potential regulatory role of as yet unidentified and untested microenvironmental cues (see Outstanding Questions). The resulting data will enable the design of physiologically relevant culture conditions for in vitro human adipose disease modeling, drug
Acknowledgments
We wish to thank Karaghen Hudson for illustrating Figure 2. We acknowledge the financial support of the Harvard Stem Cell Institute and National Institutes of Health grants U01HL100408, U01HL107440, R01DK095384, and R01DK097768 to C.A.C. and UC4DK104165 to K.K.P.
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