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• W2783249679 abstract "Adipose tissue depots can exist in close association with other organs, where they assume diverse, often non-traditional functions. In stem cell-rich skin, bone marrow, and mammary glands, adipocytes signal to and modulate organ regeneration and remodeling. Skin adipocytes and their progenitors signal to hair follicles, promoting epithelial stem cell quiescence and activation, respectively. Hair follicles signal back to adipocyte progenitors, inducing their expansion and regeneration, as in skin scars. In mammary glands and heart, adipocytes supply lipids to neighboring cells for nutritional and metabolic functions, respectively. Adipose depots adjacent to skeletal structures function to absorb mechanical shock. Adipose tissue near the surface of skin and intestine senses and responds to bacterial invasion, contributing to the body's innate immune barrier. As the recognition of diverse adipose depot functions increases, novel therapeutic approaches centered on tissue-specific adipocytes are likely to emerge for a range of cancers and regenerative, infectious, and autoimmune disorders. Adipose tissue depots can exist in close association with other organs, where they assume diverse, often non-traditional functions. In stem cell-rich skin, bone marrow, and mammary glands, adipocytes signal to and modulate organ regeneration and remodeling. Skin adipocytes and their progenitors signal to hair follicles, promoting epithelial stem cell quiescence and activation, respectively. Hair follicles signal back to adipocyte progenitors, inducing their expansion and regeneration, as in skin scars. In mammary glands and heart, adipocytes supply lipids to neighboring cells for nutritional and metabolic functions, respectively. Adipose depots adjacent to skeletal structures function to absorb mechanical shock. Adipose tissue near the surface of skin and intestine senses and responds to bacterial invasion, contributing to the body's innate immune barrier. As the recognition of diverse adipose depot functions increases, novel therapeutic approaches centered on tissue-specific adipocytes are likely to emerge for a range of cancers and regenerative, infectious, and autoimmune disorders. The storage of energy as lipids is a highly conserved mechanism shared by unicellular and multicellular organisms across evolutionary phylogeny. While prokaryotes and single-celled eukaryotes store lipids in intracellular organelles known as lipid droplets or lipid bodies, multicellular organisms developed specialized cells to house them (Driskell et al., 2014Driskell R.R. Jahoda C.A. Chuong C.M. Watt F.M. Horsley V. Defining dermal adipose tissue.Exp. Dermatol. 2014; 23: 629-631Crossref PubMed Scopus (107) Google Scholar, Ottaviani et al., 2011Ottaviani E. Malagoli D. Franceschi C. The evolution of the adipose tissue: a neglected enigma.Gen. Comp. Endocrinol. 2011; 174: 1-4Crossref PubMed Scopus (0) Google Scholar). Lipid-storing cells exist both in invertebrates and vertebrates, although rather than being homologous, they may have evolved convergently to sequester lipid from the extracellular environment (Ottaviani et al., 2011Ottaviani E. Malagoli D. Franceschi C. The evolution of the adipose tissue: a neglected enigma.Gen. Comp. Endocrinol. 2011; 174: 1-4Crossref PubMed Scopus (0) Google Scholar). In vertebrates, adipocyte-like cells have been noted already in lamprey, a group of jawless fish (Muller, 1968Muller H. Fine structure and lipid formation in fat cells of the perimeningeal tissue of lampreys under normal and experimental conditions.Z. Zellforsch. Mikrosk. Anat. 1968; 84: 585-608PubMed Google Scholar). In mammals, two principal types of adipose tissue exist, white (WAT) and brown (BAT) (Frontini and Cinti, 2010Frontini A. Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ.Cell Metab. 2010; 11: 253-256Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, Rosen and Spiegelman, 2014Rosen E.D. Spiegelman B.M. What we talk about when we talk about fat.Cell. 2014; 156: 20-44Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar). BAT develops embryonically, derived from Myf5- and Pax7-expressing precursor cells in the mesoderm that also give rise to skeletal muscle cells and a portion of white adipocytes (Lepper and Fan, 2010Lepper C. Fan C.M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells.Genesis. 2010; 48: 424-436Crossref PubMed Scopus (196) Google Scholar, Sanchez-Gurmaches et al., 2012Sanchez-Gurmaches J. Hung C.M. Sparks C.A. Tang Y. Li H. Guertin D.A. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors.Cell Metab. 2012; 16: 348-362Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, Seale et al., 2008Seale P. Bjork B. Yang W. Kajimura S. Chin S. Kuang S. Scimè A. Devarakonda S. Conroe H.M. Erdjument-Bromage H. et al.PRDM16 controls a brown fat/skeletal muscle switch.Nature. 2008; 454: 961-967Crossref PubMed Scopus (1367) Google Scholar, Wang and Seale, 2016Wang W. Seale P. Control of brown and beige fat development.Nat. Rev. Mol. Cell Biol. 2016; 17: 691-702Crossref PubMed Scopus (184) Google Scholar). Brown adipocytes, which in rodents are predominantly contained in the interscapular region, contain multilocular lipid droplets and high numbers of mitochondria, and primarily function to dissipate stored energy in the form of heat. Although in humans BAT was thought to be restricted to an interscapular depot in infants and adults chronically exposed to extreme cold, more recent evidence has suggested that brown adipocytes, and/or adipocytes possessing characteristics of both brown and white adipocytes (known as “beige” or “brite” adipocytes), may be more common in adults than had been previously appreciated (Wang and Seale, 2016Wang W. Seale P. Control of brown and beige fat development.Nat. Rev. Mol. Cell Biol. 2016; 17: 691-702Crossref PubMed Scopus (184) Google Scholar). That said, the majority of adipose tissue in mammals, including adult humans, and the focus of this review, is WAT, which is primarily composed of large adipocytes that harbor a single lipid droplet and markedly fewer mitochondria than brown adipocytes. We also discuss bone marrow adipose tissue (bmAT), which is currently thought to be distinct from either WAT or BAT (Horowitz et al., 2017Horowitz M.C. Berry R. Holtrup B. Sebo Z. Nelson T. Fretz J.A. Lindskog D. Kaplan J.L. Ables G. Rodeheffer M.S. et al.Bone marrow adipocytes.Adipocyte. 2017; 6: 193-204Crossref PubMed Scopus (41) Google Scholar). Historically, the study of WAT has centered around its principal function in controlling energy homeostasis via the storage and release of lipids in response to systemic nutritional and metabolic needs. WAT is distributed throughout the body in several distinct depots. These include visceral depots (vWAT), which in humans include omental, mesenteric, retroperitoneal, gonadal, and pericardial WAT (Wajchenberg, 2000Wajchenberg B.L. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome.Endocr. Rev. 2000; 21: 697-738Crossref PubMed Scopus (1910) Google Scholar), and are commonly associated with metabolic disorders, such as diabetes and cardiovascular disease (Shuster et al., 2012Shuster A. Patlas M. Pinthus J.H. Mourtzakis M. The clinical importance of visceral adiposity: a critical review of methods for visceral adipose tissue analysis.Br. J. Radiol. 2012; 85: 1-10Crossref PubMed Scopus (267) Google Scholar). Another highly studied depot is subcutaneous WAT (sWAT). It is located in several locations under the skin and, in humans, clusters of sWAT exist in upper (deep and superficial abdomen) and lower (gluteofemoral) body regions (Kwok et al., 2016Kwok K.H. Lam K.S. Xu A. Heterogeneity of white adipose tissue: molecular basis and clinical implications.Exp. Mol. Med. 2016; 48: e215Crossref PubMed Scopus (9) Google Scholar). Clinically, sWAT has been found to confer some beneficial effects on metabolism (Tran et al., 2008Tran T.T. Yamamoto Y. Gesta S. Kahn C.R. Beneficial effects of subcutaneous fat transplantation on metabolism.Cell Metab. 2008; 7: 410-420Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar). The differing metabolic functions of the major vWAT and sWAT depots have been the subject of numerous excellent reviews, including those by Tchkonia et al., 2013Tchkonia T. Thomou T. Zhu Y. Karagiannides I. Pothoulakis C. Jensen M.D. Kirkland J.L. Mechanisms and metabolic implications of regional differences among fat depots.Cell Metab. 2013; 17: 644-656Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar and Rosen and Spiegelman, 2014Rosen E.D. Spiegelman B.M. What we talk about when we talk about fat.Cell. 2014; 156: 20-44Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar. In addition to major WAT depots, discrete tissue-associated adipose depots are broadly distributed across the body (Figure 1). These depots are often small in size, intricate in microanatomy, closely associated with other anatomic structures, and perform novel tissue- and organ-specific functions (Kruglikov and Scherer, 2016Kruglikov I.L. Scherer P.E. Dermal adipocytes: from irrelevance to metabolic targets?.Trends Endocrinol. Metab. 2016; 27: 1-10Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Recognition of their importance is rapidly growing; yet, with few exceptions, their biology remains incompletely understood. Below we review the prominent tissue-associated adipose depots by anatomic location and highlight some of their most distinctive features. The skin consists of consecutive layers of stratified epidermis, fibroblast-rich dermis, and dermal WAT (dWAT), containing mature, unilocular white adipocytes. Skin appendages, principally hair follicles (HFs), traverse through multiple layers, and in many species, such as humans and mice, come in close contact with dWAT (Figure 1A and 1A′) (Driskell et al., 2014Driskell R.R. Jahoda C.A. Chuong C.M. Watt F.M. Horsley V. Defining dermal adipose tissue.Exp. Dermatol. 2014; 23: 629-631Crossref PubMed Scopus (107) Google Scholar). Although most mammals have a dedicated dWAT depot, its anatomy can vary substantially across species. In mice, dWAT forms a continuous layer, separated from sWAT by a striated muscle layer, also known as the panniculus carnosus (Driskell et al., 2014Driskell R.R. Jahoda C.A. Chuong C.M. Watt F.M. Horsley V. Defining dermal adipose tissue.Exp. Dermatol. 2014; 23: 629-631Crossref PubMed Scopus (107) Google Scholar). Humans largely lack this muscle layer, but plastic surgeons have long reported that fascia superficialis demarcates two distinct skin adipose compartments: namely, the superficial areolar and deep lamellar layers (Alexander and Dugdale, 1992Alexander H.G. Dugdale A.E. Fascial planes within subcutaneous fat in humans.Eur. J. Clin. Nutr. 1992; 46: 903-906PubMed Google Scholar, Gasperoni and Salgarello, 1995Gasperoni C. Salgarello M. Rationale of subdermal superficial liposuction related to the anatomy of subcutaneous fat and the superficial fascial system.Aesthet. Plast. Surg. 1995; 19: 13-20Crossref PubMed Scopus (57) Google Scholar). These layers of skin-associated WAT differ in cellular distribution and metabolic activity (Sbarbati et al., 2010Sbarbati A. Accorsi D. Benati D. Marchetti L. Orsini G. Rigotti G. Panettiere P. Subcutaneous adipose tissue classification.Eur. J. Histochem. 2010; 54: e48Crossref PubMed Scopus (0) Google Scholar, Smith et al., 2001Smith S.R. Lovejoy J.C. Greenway F. Ryan D. deJonge L. de la Bretonne J. Volafova J. Bray G.A. Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity.Metabolism. 2001; 50: 425-435Abstract Full Text PDF PubMed Scopus (403) Google Scholar, Walker et al., 2007Walker G.E. Verti B. Marzullo P. Savia G. Mencarelli M. Zurleni F. Liuzzi A. Di Blasio A.M. Deep subcutaneous adipose tissue: a distinct abdominal adipose depot.Obesity (Silver Spring). 2007; 15: 1933-1943Crossref PubMed Scopus (0) Google Scholar). Pigs contain three layers of skin-associated WAT, each separated by layers of fascia, with adipocytes in the outer and middle layers having distinct cellular, enzymatic, and lipidomic profiles (Anderson et al., 1972Anderson D.B. Kauffman R.G. Kastenschmidt L.L. Lipogenic enzyme activities and cellularity of porcine adipose tissue from various anatomical locations.J. Lipid Res. 1972; 13: 593-599Abstract Full Text PDF PubMed Google Scholar, Hilditch and Stainsby, 1935Hilditch T.P. Stainsby W.J. The body fats of the pig: progressive hydrogenation as an aid in the study of glyceride structure.Biochem. J. 1935; 29: 90-99Crossref PubMed Google Scholar, Monziols et al., 2007Monziols M. Bonneau M. Davenel A. Kouba M. Comparison of the lipid content and fatty acid composition of intermuscular and subcutaneous adipose tissues in pig carcasses.Meat Sci. 2007; 76: 54-60Crossref PubMed Scopus (61) Google Scholar). A signature feature of dWAT is its striking cyclic size fluctuations, which occur in parallel with HF cycling (Chase et al., 1953Chase H.B. Montagna W. Malone J.D. Changes in the skin in relation to the hair growth cycle.Anat. Rec. 1953; 116: 75-81Crossref PubMed Scopus (86) Google Scholar, Wojciechowicz et al., 2008Wojciechowicz K. Markiewicz E. Jahoda C.A. C/EBPalpha identifies differentiating preadipocytes around hair follicles in foetal and neonatal rat and mouse skin.Exp. Dermatol. 2008; 17: 675-680Crossref PubMed Scopus (0) Google Scholar, Wojciechowicz et al., 2013Wojciechowicz K. Gledhill K. Ambler C.A. Manning C.B. Jahoda C.A. Development of the mouse dermal adipose layer occurs independently of subcutaneous adipose tissue and is marked by restricted early expression of FABP4.PLoS One. 2013; 8: e59811Crossref PubMed Scopus (43) Google Scholar). HFs repetitively make new hairs via a three-phase regeneration cycle involving (1) growth (known as anagen), during which HFs elongate via epithelial cell proliferation and the dWAT layer prominently expands in thickness; (2) regression (known as catagen), when HFs involute largely via apoptosis and dWAT recedes; and (3) quiescence (known as telogen) when HFs are small and inactive and dWAT is at its thinnest (Figure 2) (Stenn and Paus, 2001Stenn K.S. Paus R. Controls of hair follicle cycling.Physiol. Rev. 2001; 81: 449-494Crossref PubMed Scopus (958) Google Scholar). Cyclic dWAT expansion results both from hypertrophy of pre-existing adipocytes and hyperplasia, which involves proliferation of adipocyte precursors (APs) that subsequently differentiate into lipid-laden, unilocular adipocytes (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis.Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Google Scholar, Zhang et al., 2016Zhang B. Tsai P.C. Gonzalez-Celeiro M. Chung O. Boumard B. Perdigoto C.N. Ezhkova E. Hsu Y.C. Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog.Genes Dev. 2016; 30: 2325-2338Crossref PubMed Scopus (32) Google Scholar). In mouse dWAT, several populations of APs are recognized. Similar to other WAT depots, dermal APs are defined by the expression of the cellular surface markers CD34, CD29, and Sca1 (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, Rodeheffer et al., 2008Rodeheffer M.S. Birsoy K. Friedman J.M. Identification of white adipocyte progenitor cells in vivo.Cell. 2008; 135: 240-249Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar). Among these APs, CD24+ cells represent an adipocyte stem cell (ASC) population, while CD24− cells are committed pre-adipocytes (Berry et al., 2013Berry D.C. Stenesen D. Zeve D. Graff J.M. The developmental origins of adipose tissue.Development. 2013; 140: 3939-3949Crossref PubMed Scopus (131) Google Scholar, Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis.Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Google Scholar). Although both CD24+ and CD24− subsets of APs proliferate prior to anagen, the CD24+ ASC population preferentially expands, resulting in the generation of ∼20% new adipocytes (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis.Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Google Scholar). Proliferation of both ASCs and pre-adipocytes is Pdgfa-dependent, and dWAT expansion at this stage is abrogated in mice with a mesenchymal cell-specific deletion of Pdgfa (Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis.Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Google Scholar). HF elongation and dWAT expansion during anagen are not only concomitant, but functionally linked, providing a prime example of cross-regulation between epithelial and adipose cell lineages (Figure 2A). Defects in dermal adipogenesis affect HF regeneration; hair cycle progression becomes disrupted upon pharmacological inhibition of the adipocyte differentiation regulatory factor Pparγ and after transplantation of normal skin onto Ebf1 mutant mice, in which dermal APs are reduced (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Conversely, grafting purified APs into normal telogen skin is sufficient to activate a new hair growth cycle (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Unlike in Ebf1 mutants, hair cycle progresses normally in A-Zip mice that lack mature adipocytes but feature elevated AP numbers (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling.Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, Rodeheffer et al., 2008Rodeheffer M.S. Birsoy K. Friedman J.M. Identification of white adipocyte progenitor cells in vivo.Cell. 2008; 135: 240-249Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar). These data show that dermal APs, rather than mature adipocytes, promote new hair cycle entry by HFs. By contrast, mature dermal adipocytes supply telogen HFs with long-range inhibitory signals that simultaneously stall hair regeneration across large stretches of skin (Plikus et al., 2008Plikus M.V. Mayer J.A. de la Cruz D. Baker R.E. Maini P.K. Maxson R. Chuong C.M. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.Nature. 2008; 451: 340-344Crossref PubMed Scopus (416) Google Scholar). This role for dermal adipocytes was identified in studies on natural hair cycle in mice; certain groups of telogen HFs are competent to quickly reenter anagen when challenged with physiological or exogenous growth-activating signals, such as hair plucking (Chen et al., 2015Chen C.C. Wang L. Plikus M.V. Jiang T.X. Murray P.J. Ramos R. Guerrero-Juarez C.F. Hughes M.W. Lee O.K. Shi S. et al.Organ-level quorum sensing directs regeneration in hair stem cell populations.Cell. 2015; 161: 277-290Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), while other groups of telogen HFs are refractory to the very same stimuli and fail to regenerate. Further observations showed that during early telogen, HFs are refractory and acquire competent state only after one month, and that this is associated with prominent downregulation of Bone morphogenetic protein 2 (Bmp2) expression by adjacent dermal adipocytes (Figures 2C and 2D). BMP signaling maintains quiescence of HF stem cells and adipose-derived Bmp2 contributes to highly quiescent, refractory telogen state. Skin-specific overexpression of the soluble BMP antagonist Noggin is sufficient to largely abolish telogen refractivity, leading to precocious hair cycle reentry by HFs (Plikus and Chuong, 2014Plikus M.V. Chuong C.M. Macroenvironmental regulation of hair cycling and collective regenerative behavior.Cold Spring Harb. Perspect. Med. 2014; 4: a015198Crossref PubMed Scopus (29) Google Scholar, Plikus et al., 2008Plikus M.V. Mayer J.A. de la Cruz D. Baker R.E. Maini P.K. Maxson R. Chuong C.M. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.Nature. 2008; 451: 340-344Crossref PubMed Scopus (416) Google Scholar). Hair cycle-coupled dWAT expansion is also modulated by epithelial Wnt activity (Donati et al., 2014Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.Proc. Natl. Acad. Sci. USA. 2014; 111: E1501-E1509Crossref PubMed Scopus (73) Google Scholar) and Shh signals (Zhang et al., 2016Zhang B. Tsai P.C. Gonzalez-Celeiro M. Chung O. Boumard B. Perdigoto C.N. Ezhkova E. Hsu Y.C. Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog.Genes Dev. 2016; 30: 2325-2338Crossref PubMed Scopus (32) Google Scholar) (Figure 2A). During HF morphogenesis and regeneration, inhibition of canonical Wnt signaling in epithelial skin cells suppresses adipogenesis, while its ectopic activation increases dWAT expansion, even in the absence of HFs. Responding to Wnt activation in vitro, epithelial cells secrete pro-adipogenic factors, suggesting a potential mechanism by which epithelial cells may control dWAT expansion in parallel with anagen entry. Donati et al., 2014Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.Proc. Natl. Acad. Sci. USA. 2014; 111: E1501-E1509Crossref PubMed Scopus (73) Google Scholar identified BMP and insulin-like growth factor (IGF) ligands as the putative Wnt-controlled epithelial pro-adipogenic factors. Another recent study identified pro-adipogenic effect of HF-derived Shh ligands (Zhang et al., 2016Zhang B. Tsai P.C. Gonzalez-Celeiro M. Chung O. Boumard B. Perdigoto C.N. Ezhkova E. Hsu Y.C. Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog.Genes Dev. 2016; 30: 2325-2338Crossref PubMed Scopus (32) Google Scholar), adding the Hedgehog pathway to the list of signals shared between HFs and dWAT. In addition to local triggers, dWAT can expand in response to systemic cold stress (Kasza et al., 2014Kasza I. Suh Y. Wollny D. Clark R.J. Roopra A. Colman R.J. MacDougald O.A. Shedd T.A. Nelson D.W. Yen M.I. et al.Syndecan-1 is required to maintain intradermal fat and prevent cold stress.PLoS Genet. 2014; 10: e1004514Crossref PubMed Scopus (45) Google Scholar). Compared with normal animals, mice lacking syndecan-1, a heparin sulfate proteoglycan, display dWAT size reduction and compromised cold stress responses at room temperature (21°C) that induces moderate thermal shock, but not at thermo-neutral conditions (31°C). Boosting adipogenesis with the Pparγ agonist rosiglitazone rescues both the dWAT thickness and cold stress response phenotypes in syndecan-1 null mice. While the role of skin in systemic thermoregulation is not fully understood (Romanovsky, 2014Romanovsky A.A. Skin temperature: its role in thermoregulation.Acta Physiol. 2014; 210: 498-507Crossref PubMed Scopus (142) Google Scholar), the syndecan-1 study suggests that dWAT is important for this homeostatic process. The mechanism by which dWAT responds to cold stress is an exciting future direction for the field. dWAT also plays a major role in several aspects of skin wound healing. Wound repair typically occurs in three sequential stages: inflammation, proliferation, and remodeling (Gurtner et al., 2008Gurtner G.C. Werner S. Barrandon Y. Longaker M.T. Wound repair and regeneration.Nature. 2008; 453: 314-321Crossref PubMed Scopus (2619) Google Scholar). This process can be modeled in mice, with different injury sizes resulting in distinct repair outcomes. Regeneration of HFs and lipid-filled adipocytes occur during repair of large but not small wounds (Ito et al., 2007Ito M. Yang Z. Andl T. Cui C. Kim N. Millar S.E. Cotsarelis G. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding.Nature. 2007; 447: 316-320Crossref PubMed Scopus (580) Google Scholar, Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Regeneration of fat cells from myofibroblasts during wound healing.Science. 2017; 355: 748-752Crossref PubMed Scopus (136) Google Scholar). Lineage studies using Sm22-Cre and Sma-CreER mouse models showed that the majority of newly formed adipocytes that are generated in large healing wounds derive from contractile fibroblasts, known as myofibroblasts (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Regeneration of fat cells from myofibroblasts during wound healing.Science. 2017; 355: 748-752Crossref PubMed Scopus (136) Google Scholar). De novo adipogenesis in this case is driven by BMP signals generated by new anagen-stage HFs and depends on activation of Zfp423, the key transcriptional regulator of adipose lineage commitment (Gupta et al., 2010Gupta R.K. Arany Z. Seale P. Mepani R.J. Ye L. Conroe H.M. Roby Y.A. Kulaga H. Reed R.R. Spiegelman B.M. Transcriptional control of preadipocyte determination by Zfp423.Nature. 2010; 464: 619-623Crossref PubMed Scopus (285) Google Scholar, Shao et al., 2017Shao M. Hepler C. Vishvanath L. MacPherson K.A. Busbuso N.C. Gupta R.K. Fetal development of subcutaneous white adipose tissue is dependent on Zfp423.Mol. Metab. 2017; 6: 111-124Crossref PubMed Scopus (17) Google Scholar). New adipocyte formation in response to signals from HFs during wound healing thus provides further support for the notion of bidirectional signaling between epithelial and adipocyte lineages (Donati et al., 2014Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.Proc. Natl. Acad. Sci. USA. 2014; 111: E1501-E1509Crossref PubMed Scopus (73) Google Scholar). Anagen HFs derived from human scalp and BMP can also induce human keloid scar fibroblasts to undergo adipogenesis in vitro (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Regeneration of fat cells from myofibroblasts during wound healing.Science. 2017; 355: 748-752Crossref PubMed Scopus (136) Google Scholar), suggesting at least partial conservation of this phenomenon between mice and humans. Several studies suggest that dWAT is an active participant in wound repair, though our understanding of the specific roles played by adipocyte lineage cells in the process is not yet fully understood. Transplantation of heterogeneous populations of adipose-derived mesenchymal cells into dermal wounds accelerates healing (Kim et al., 2007Kim W.S. Park B.S. Sung J.H. Yang J.M. Park S.B. Kwak S.J. Park J.S. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts.J. Dermatol. Sci. 2007; 48: 15-24Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar), although further studies are needed to clarify whether this function could be attributed to a pure population of adipocyte precursor cells. When adipogenesis is inhibited via pharmacological and genetic means, extracellular matrix deposition and fibroblast recruitment into the wound bed are impaired (Schmidt and Horsley, 2013Schmidt B.A. Horsley V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing.Development. 2013; 140: 1517-1527Crossref PubMed Scopus (127) Google Scholar), suggesting that adipocyte lineage cells enhance normal healing, likely via paracrine signaling. Indeed, several adipocyte-derived factors, or adipokines, have been implicated i" @default.
• W2783249679 created "2018-01-26" @default.
• W2783249679 creator A5037405025 @default.
• W2783249679 creator A5040295525 @default.
• W2783249679 creator A5053553128 @default.
• W2783249679 creator A5054754643 @default.
• W2783249679 date "2018-01-01" @default.
• W2783249679 modified "2023-10-15" @default.
• W2783249679 title "Anatomical, Physiological, and Functional Diversity of Adipose Tissue" @default.
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