Review
Genetic and epigenetic control of adipose development

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Abstract

White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via Ucp1 to maintain body temperature. BAT and subcutaneous WAT develop perinatally while visceral WAT forms after birth from precursors expressing distinct markers, such as Myf5, Pref-1, Wt1, and Prx1, depending on the anatomical location. In addition to the embryonic adipose precursors, a pool of endothelial cells or mural cells expressing Pparγ, Pdgfrβ, Sma and Zfp423 may become adipocytes during WAT expansion in adults. Several markers, such as Cd29, Cd34, Sca1, Cd24, Pdgfrα and Pref-1 are detected in adult WAT SVF cells that can be differentiated into adipocytes. However, potential heterogeneity and differences in developmental stage of these cells are not clear. Beige cells form in a depot- and condition-specific manner by de novo differentiation of precursors or by transdifferentiation. Thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes Prdm16, Zfp516, Pgc1α and Ebf2. Moreover, through changing the chromatin landscape, histone methyltransferases, such as Mll3/4 and Ehmt1, as well as demethylases, such as Lsd1, play an important role in regulating the thermogenic gene program. With the presence of BAT and beige/brite cells in human adults, increasing thermogenic activity of BAT and BAT-like tissues may help promote energy expenditure to combat obesity.

Introduction

Adipose tissue plays a crucial role in mammalian metabolism. White adipose tissue (WAT) stores excess energy as triglycerides (TAGs) in a unilocular lipid droplet within adipocytes. WAT is also considered an endocrine organ that secretes adipokines to affect various processes including food intake and insulin sensitivity [1]. In contrast, brown adipose tissue (BAT) serves mostly as an oxidative tissue to regulate body temperature but also is beneficial to glucose and lipid homeostasis [2,3]. Brown adipocytes contain multilocular lipid droplets and abundant mitochondria with the unique protein Ucp1, which uncouples substrate oxidation from ATP synthesis to generate heat. In rodents, BAT is located primarily in the interscapular region, whereas WAT depots are found in various but specific regions in the body. More recently, “thermogenic” Ucp1 positive adipocytes, so called “beige” or “brite” cells, have been found in mainly subcutaneous WAT, following cold exposure or stimulation by β3-adrenergic agonists, drawing much attention due to their potential benefit in weight-loss [[4], [5], [6]]. This review will focus on the developmental origin of adipocytes, highlighting transcriptional and epigenetic control of brown and beige adipogenesis.

Section snippets

Developmental origin of WAT

Researchers have long puzzled over the origin of adipose tissue as well as its development. WAT is categorized into subcutaneous and visceral WAT. Subcutaneous WAT is found in inguinal (posterior) and intrascapular (anterior) regions, whereas visceral WAT is found in perigonadal (often referred as epididymal WAT in males), perirenal, epicardial, retroperitoneal, mesenteric and omental regions (shown in Fig. 1A). Subcutaneous and visceral WAT are believed to have distinct response mechanisms as

Isolation of adipose precursors in SVF of adult WAT

In adipose tissue, in addition to adipocytes, there are multiple other types of cells, such as preadipocytes or adipose precursors, stem cells, fibroblasts, endothelial cells, macrophages, and leukocytes, often collectively called SVF based on the separation from lipid-containing adipocytes. Heterogeneity within SVF has long been an obstacle in isolating and characterizing pure precursor populations. Fluorescence activated cell sorting (FACS) using several stem cell markers allowed researchers

Developmental origin of BAT

Given the morphological and functional differences between brown and white adipocytes, these two types of adipocytes may have different developmental origins. Indeed, interscapular BAT (iBAT) formation in mice starts earlier than WAT during embryogenesis and BAT is fully thermogenically-competent at birth, providing a defense mechanism against cold stress in newborns. As early as at E9.5, cells expressing engrailed 1 (En1), a homeobox domain containing gene that marks the central dermomyotome,

“Browning” of WAT

Typical adipocytes in WAT have a unilocular lipid droplet morphology and few mitochondria (summarized in Fig. 1B). Upon cold exposure or β-adrenergic stimulation, some cells in WAT acquire Ucp1 expression and have multilocular lipid droplets and abundant mitochondria. Thus, WAT may undergo “browning” with the appearance of thermogenic “beige” or “brite” adipocytes that share some similar features with brown adipocytes [[4], [5], [6]]. Historically, the first evidence of existence of these

Transcriptional regulation of BAT development and “browning” of WAT

Since BAT mass is inversely correlated with BMI in humans, increasing BAT activity could be a promising strategy for weight-loss and management of obesity-associated diseases [2,68]. With greatly higher mass of WAT in comparison to BAT, increasing WAT “browning” may improve insulin sensitivity and reduce weight gain under high fat diet as shown in mice [3,[69], [70], [71], [72], [73]]. This section summarizes the transcriptional regulation involved in BAT development and “browning” of WAT. The

Epigenetic control of the BAT gene program

As in most biological processes, interactions between genes and the environment, such as temperature or diet [100,101], may influence BAT gene expression and thermogenesis, by involving epigenetic events, i.e., heritable changes in traits without changes in DNA sequence. The broad umbrella of epigenetics research includes both DNA and histone modifications as well as microRNA and long noncoding RNA (lncRNA) either inhibiting or enhancing transcription. In this regard, DNA is wrapped around

Future directions

Understanding WAT and BAT development and the underlying mechanism to promote “browning” of WAT may provide targets for combating and preventing obesity and associated diseases. For some of the markers of adipose precursors recently identified, further investigation is needed to establish their contribution in embryogenic versus postnatal adipogenesis. Better FACS using multiple markers coupled with immunostaining and lineage tracing approaches will be needed. Moreover, single cell level

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Acknowledgements

The research programs of the authors have been supported in part by an NIDDK (1R01DK095338-01A1) grant to H.S.S. The authors declare no competing financial interests.

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