Microenvironmental Control of Adipocyte Fate and Function

doi:10.1016/j.tcb.2016.05.005

Trends in Cell Biology

Volume 26, Issue 10, October 2016, Pages 745-755

https://doi.org/10.1016/j.tcb.2016.05.005 Get rights and content

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Subcutaneous and visceral adipose depots are innervated, vascularized endocrine organs comprising multipotent progenitor cells and differentiated adipocytes.

Brown adipocytes differ from white adipocytes in their morphology, functional capacities, and depot locations, but ‘beige’ or ‘brite’ adipocytes, which share characteristics of both white and brown adipocytes, are found in some white and brown depots.

Adipocytes can expand several-thousand fold in size during cellular maturation and are electrically and metabolically coupled by gap junctions.

Biophysical cues from the microenvironment modulate adipocyte differentiation, growth, and function.

Altered adipocyte microenvironments in obesity are associated with type 2 diabetes mellitus, breast cancer, and other diseases, suggesting that microenvironmental factors in adipose tissue can be pathogenic.

The properties of tissue-specific microenvironments vary widely in the human body and demonstrably influence the structure and function of many cell types. Adipocytes are no exception, responding to cues in specialized niches to perform vital metabolic and endocrine functions. The adipose microenvironment is remodeled during tissue expansion to maintain the structural and functional integrity of the tissue and disrupted remodeling in obesity contributes to the progression of metabolic syndrome, breast cancer, and other malignancies. The increasing incidence of these obesity-related diseases and the recent focus on improved in vitro models of human tissue biology underscore growing interest in the regulatory role of adipocyte microenvironments in health and disease.

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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Maintaining healthy adipose tissue is crucial for metabolic health, requiring a deeper understanding of adipocyte development and response to high-calorie diets. This study highlights the importance of TET3 during white adipose tissue (WAT) development and expansion. Selective depletion of Tet3 in adipose precursor cells (APCs) reduces adipogenesis, protects against diet-induced adipose expansion, and enhances whole-body metabolism. Transcriptomic analysis of wild-type and Tet3 knockout (KO) APCs unveiled TET3 target genes, including Pparg and several genes linked to the extracellular matrix, pivotal for adipogenesis and remodeling. DNA methylation profiling and functional studies underscore the importance of DNA demethylation in gene regulation. Remarkably, targeted DNA demethylation at the Pparg promoter restored its transcription. In conclusion, TET3 significantly governs adipogenesis and diet-induced adipose expansion by regulating key target genes in APCs.
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Citation Excerpt :
In conclusion, there is a large body of literature showing that the composition and mechanical properties of the ECM have an essential role in AT remodeling and healthy expansion. Most research so far has focused on the influence of matrix stiffness on adipogenesis, and we refer the interested readers to other excellent reviews on this topic (Mor-Yossef Moldovan et al., 2019; Pope et al., 2016; Yuan et al., 2015). In this review article, we sought to draw attention to the molecules and mechanisms of mechanotransduction involved in mature adipocyte function and fate.
Adipose tissue (AT) is a complex organ, with multiple functions that are essential for maintaining metabolic health. A feature of AT is its capability to expand in response to physiological challenges, such as pregnancy and aging, and during chronic states of positive energy balance occurring throughout life. AT grows through adipogenesis and/or an increase in the size of existing adipocytes. One process that is required for healthy AT growth is the remodeling of the extracellular matrix (ECM), which is a necessary step to restore mechanical homeostasis and maintain tissue integrity and functionality. While the relationship between mechanobiology and adipogenesis is now well recognized, less is known about the role of adipocyte mechanosignaling pathways in AT growth. In this review article, we first summarize evidence linking ECM remodelling to AT expansion and how its perturbation is associated to a metabolically unhealthy phenotype. Subsequently, we highlight findings suggesting that molecules involved in the dynamic, bidirectional process (mechanoreciprocity) enabling adipocytes to sense changes in the mechanical properties of the ECM are interconnected to pathways regulating lipid metabolism. Finally, we discuss processes through which aging may influence the ability of adipocytes to appropriately respond to alterations in ECM composition.
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Trends in Cell Biology

ReviewMicroenvironmental Control of Adipocyte Fate and Function

Trends

Section snippets

Adipose Depots and Functions

The Developing Adipocyte Niche

Adipocyte Interactions with the Extracellular Matrix

Adipose Cytoarchitecture and Adipocyte–Adipocyte Interactions

Mechanotransduction in Adipocytes

Heterotypic Cell Interactions Within Adipose Depots

Adipocyte Microenvironments in Disease

Applying Regulatory Principles of Adipocyte Microenvironments

Concluding Remarks

Acknowledgments

FEBS Lett.

Mol. Cell. Endocrinol.

Trends Endocrinol. Metab.

J. Biomech.

J. Biomech.

Endocrinol. Nutr. Órgano Soc. Esp. Endocrinol. Nutr.

Free Radic. Biol. Med.

Trends Endocrinol. Metab.

Cell Metab.

Cell Metab.

Early Hum. Dev.

Mol. Aspects Med.

Cell

Acta Biomater.

Cell Metab.

Dev. Cell

J. Biol. Chem.

J. Thromb. Haemost.

Cell

Biochem. Biophys. Res. Commun.

Cell

Cell

Cell

Biomaterials

Metabolism

Microbes Infect.

Biochim. Biophys. Acta

Biophys. J.

Biochem. Biophys. Res. Commun.

Curr. Biol.

J. Biosci. Bioeng.

Cell Metab.

J. Lipid Res.

Trends Endocrinol. Metab.

Cell Metab.

Mol. Cell. Endocrinol.

Cell

Cell

Cell

Cell Metab.

Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults

Am. J. Clin. Nutr.

Bi-directional interconversion of brite and white adipocytes

Nat. Cell Biol.

White-to-brown metabolic conversion of human adipocytes by JAK inhibition

Nat. Cell Biol.

Non-shivering thermogenesis and brown adipose tissue in the human new-born infant

Nature

High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity

Diabetes

The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells

Diabetologia

Elevated blood pressure in transgenic lipoatrophic mice and altered vascular function

Hypertension

Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis

Circulation

Human cold adaptation: an unfinished agenda

Am. J. Hum. Biol.

Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies

Stem Cell Rev.

Review
Microenvironmental Control of Adipocyte Fate and Function