Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewGenetic and epigenetic control of adipose development☆
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.
References (124)
- et al.
What we talk about when we talk about fat
Cell
(2014) - et al.
Brown and beige fat: physiological roles beyond heat generation
Cell Metab.
(2015) - et al.
Emerging complexities in adipocyte origins and identity
Trends Cell Biol.
(2016) The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity
Cell Metab.
(2016)Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance
Cell Metab.
(2014)Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion
Cell Rep.
(2014)- et al.
Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation
Cell
(1993) - et al.
The chronology of adipose tissue appearance and distribution in the human fetus
Early Hum. Dev.
(1984) - et al.
Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells
Stem Cell Rep.
(2014) - et al.
Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre
Stem Cell Rep.
(2015)
Pericytes: developmental, physiological, and pathological perspectives, problems, and promises
Dev. Cell
Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis
Cell Rep.
Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma
Cell
PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism
Blood
Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Cell
Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells
Cell Metab.
Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice
Cell Metab.
Amplification of adipogenic commitment by VSTM2A
Cell Rep.
In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding
Cell Metab.
Identification of white adipocyte progenitor cells in vivo
Cell
Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling
Cell
A PDGFRα-mediated switch toward CD9(high) adipocyte progenitors controls obesity-induced adipose tissue fibrosis
Cell Metab.
Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse
Dev. Biol.
Brown adipose tissue in the parametrial fat pad of the mouse
FEBS Lett.
Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human
Cell
Ribosomal profiling provides evidence for a smooth muscle-like origin of beige adipocytes
Cell Metab.
4-Factors affecting brown adipose tissue activity in animals and man
Clin. Endocrinol. Metab.
The changed metabolic world with human brown adipose tissue: therapeutic visions
Cell Metab.
Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat
Mol. Cell
Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis
Cell
Zfp423 maintains white adipocyte identity through suppression of the beige cell thermogenic gene program
Cell Metab.
β-Adrenergic activation of p38 MAP kinase in adipocytes cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 map kinase
J. Biol. Chem.
A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis
Cell
PPARγ is required for placental, cardiac, and adipose tissue development
Mol. Cell
Transcriptional control of brown fat determination by PRDM16
Cell Metab.
LSD1 interacts with Zfp516 to promote UCP1 transcription and brown fat program
Cell Rep.
Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice
Cell Metab.
Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle
Cell Metab.
IRF4 is a key thermogenic transcriptional partner of PGC-1α
Cell
Interferon-regulatory factors (IRFs) are transcriptional regulators of adipogenesis
Cell Metab.
Cold-inducible SIRT6 regulates thermogenesis of brown and beige fat
Cell Rep.
EBF2 determines and maintains brown adipocyte identity
Cell Metab.
Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes
Cell
Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling
Cell Metab.
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
J. Clin. Invest.
PRDM16 controls a brown fat/skeletal muscle switch
Nature
Control of brown and beige fat development
Nat. Rev. Mol. Cell Biol.
Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity
Nat. Cell Biol.
Intrinsic differences in adipocyte precursor cells from different white fat depots
Diabetes
Tracking adipogenesis during white adipose tissue development, expansion and regeneration
Nat. Med.
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2022, Journal of ProteomicsCitation Excerpt :Not only can it be used as a biomarker for breeding programs, but the proteomic information in livestock species can also be used to define animal models [23,24]. Several factors affect adipogenesis and fat development, including epigenetics, signaling pathways, and nutritional levels [25–29]. Studies in Chinese indigenous fatty pig breeds have shown that adipose tissue undergoes intense developmental changes (hyperplasia and hypertrophy) during growth [30,31].
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2022, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsDefective brown adipose tissue thermogenesis and impaired glucose metabolism in mice lacking Letmd1
2021, Cell ReportsCitation Excerpt :Efforts to identify brown-adipocyte-lineage-specific transcriptional regulators over the past decade have led to important molecules such as Prdm16 and Ebf2 (Rajakumari et al., 2013; Seale et al., 2007). Ebf2 has been proposed to act as a pioneer factor early in BAT differentiation and is capable of binding target genomic sites in a closed chromatin state and recruiting the chromatin remodeler Brg1 and its associated BAF complex, with other transcriptional regulators such as PPARγ, Prdm16, and PGC1α becoming involved later (Gulyaeva et al., 2019; Shapira et al., 2017). Letmd1 is not a transcriptional regulator in itself but it physically interacts with Brg1 (Figure 5C), and the loss of Letmd1 results in reduced levels of Brg1 and Ebf2 (Figure 6D).
Formation of thermogenic adipocytes: What we have learned from pigs
2021, Fundamental ResearchCitation Excerpt :As a transcriptional co-component, PRDM16 plays a substantial role in regulating brown fat cell fate and beige fat function [49]. Specifically, PRDM16 drives brown/beige adipocyte differentiation through interactions with adipogenic transcription factors C/EBPβ, PPARγ, zinc finger protein 516 (ZFP516) and euchromatic histone-lysine N-methyltransferase 1 (EHMT1) [50,51]. EHMT1, a BAT-enriched lysine methyltransferase in the PRDM16 transcriptional complex, has also been shown to control brown adipocyte fate, as brown adipocyte-specific deletion of EHMT1 causes a loss of brown adipocyte features, while EHMT1 expression activates the BAT-selective program by stabilizing the PRDM16 protein [52].
TET1 promotes RXRα expression and adipogenesis through DNA demethylation
2021, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :Similarly, western blot and dot blot results confirmed the increased level of TET1 protein and increased 5hmC in the differentiation process (Fig. 3B). Mouse preadipocyte from stromal vascular faction (SVF) of inguinal white adipose tissue (iWAT) is a more physiologically relevant model [5]. The strong upregulation of Tet1 and a mild increase of Tet2 after differentiation were detected (Fig. 3C).
Integrating network pharmacology and animal experimental validation to investigate the action mechanism of oleanolic acid in obesity
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This article is part of a Special Issue entitled Brown and Beige Fat: From Molecules to Physiology Guest Editor: Paul Cohen.