New perspectives on obesity-induced adipose tissue fibrosis and related clinical manifestations

Abstract

Adipose tissue is a complex heterogeneous tissue composed of adipocytes along with several non-adipocyte populations, including blood, stromal, endothelial, and progenitor cells, as well as extracellular matrix (ECM) components. As obesity progresses, the adipose tissue expands dynamically through adipocyte hypertrophy and/or hyperplasia. This expansion requires continuous ECM remodeling to properly accommodate the size increase as well as functional changes. Upon reaching a hypertrophic threshold beyond the adipocyte buffering capacity, excess ECM components are deposited, causing fibrosis and ultimately resulting in unhealthy metabolic maladaptation. These complex ECM remodeling processes in adipose tissues are regulated by the local environment, several key mediators, and genetic factors that are closely linked to insulin sensitivity. It is crucial to understand how adipocytes interact with nonadipocyte populations and various mediators (i.e., immune cells, ECM components, and adipokines) during these processes. This mini-review provides an overview of the latest research into the biology of obesity-induced adipose tissue fibrosis and its related clinical manifestations, providing insight for further studies aimed at controlling metabolic syndrome and its comorbidities.

Introduction

Obesity and its related health complications are major public health challenges worldwide. The progression of obesity is closely associated with the enlargement of adipose tissue, which responds dynamically and rapidly to a variety of internal and external stimuli [1]. As obesity progresses, the adipose tissue dynamically expands by increasing its lipid storage capacity (hypertrophy) and/or increasing the number of adipocytes (hyperplasia), thereby necessitating ongoing extracellular matrix (ECM) remodeling to accommodate this expansion [2-5]. Maintenance of marked flexibility in the ECM environment is a prerequisite for healthy adipose tissue. This flexibility is thought to characterize the tissue expansion of “healthy” adipose tissue, representing so-called “metabolic adaptation”. However, after the hypertrophic threshold exceeds the adipocyte buffering capacity, ectopic lipid deposition in adipose tissue induces persistent hypoxia, fibrosis, and necrotic adipocyte death, ultimately leading to “unhealthy” adipose tissue expansion, known as “metabolic maladaptation” [5, 6] (Fig. 1). Excess ECM deposition in the form of fibrosis in adipose tissue is characteristic of subjects with obesity and is thought to contribute to systemic metabolic disturbances that are features of obesity and type 2 diabetes. However, adipocyte size and fibrosis are inversely correlated in humans [7, 8]. Thus, the consequences of the fibrosis in adipose tissue remain a controversial issue [9].

Fig. 1

Metabolic adaptation and maladaptation during obesity progression

Unhealthy WAT expansion leads to metabolic maladaptation, which ultimately leads to adipose tissue fibrosis and metabolic dysfunction.

Thermogenic adipocytes, such as brown and beige adipocytes, play pivotal roles in the adaptation of adipose tissues to worsening obesity. Recent studies revealed that adipogenesis of beige adipocytes in white adipose tissue (WAT), the so-called browning phenomenon, effectively alleviates adipose tissue fibrosis [10, 11]. Promoting thermogenic brown/beige adipocytes counteracts obesity and its associated adipose tissue fibrosis [12-14]. CD81, recently identified as a beige fat progenitor marker, forms a complex with αV/β1 and αV/β5 integrins [15]. CD81 was shown to control the proliferation of beige adipocyte progenitors and mediate adipose tissue remodeling by activating integrin-focal adhesion kinase (FAK) signaling [15]. Furthermore, certain drugs (CL316,243, rosiglitazone, berberine, etc.) and food types can induce the browning, leading to beneficial effects in terms of preventing obesity [16, 17]. However, effective and safe clinical methods to promote brown/beige adipocytes have yet to be established in humans.

The features of obesity-related WAT dysfunction include unresolved inflammation [18], local hypoxia in adipose tissue [19], inappropriate ECM remodeling, alterations in the adipokine secretome [20], and insufficient angiogenic potential [5, 21]. Among these features, we focus on the mechanism of ECM remodeling associated with adipose tissue fibrosis in this review (Fig. 1).

Progenitors of Adipocytes and the Origin of ECM

It was initially established that the CD34⁺/CD31^– cell population from the human WAT stromal vascular fraction (SVF) has adipogenic capacity [22]. Recent flow cytometric approaches and single-cell RNA sequencing analyses have revealed progenitors expressing several surface markers exhibit adipogenic commitment [23-27]. Notably, the expression level of CD9 defines two distinct progenitor populations. Adipocytes expressing platelet-derived growth factor receptor-α-positive (PDGFRα⁺) CD9^high progenitors were reportedly prone to producing ECM and showed a fibrogenic phenotype in the visceral adipose tissue of obese individuals, whereas PDGFRα⁺CD9^low progenitors were committed to the adipogenic phenotype [28]. Myofibroblasts, which originate from adipocytes expressing adiponectin, contribute to ECM production in the dermal WAT [29]. In addition, macrophages and mature adipocytes produce pro-fibrotic collagens, fibronectin, and tenascin-C, which in turn accommodate increases in the size of adipose tissue and induce the production of ECM [10, 30]. Importantly, myocardin-related transcription factor A (MRTFA) is a critical regulator of the myofibroblast differentiation that induces α-SMA and collagens [31]. MRTFA deficiency in mice shifts the Sca1^–, Sma⁺, and ITGA5⁺ perivascular progenitors to become fibrogenic adipocyte precursor cells, thereby protecting against chronic obesity-induced fibrosis and its accompanying metabolic dysfunction, without altering energy expenditure [32]. Furthermore, lineage tracing studies in rodents revealed that WAT expansion in obese subjects occurs in an adipogenic-depot and in a gender-dependent manner, suggesting the importance of sex hormones in maintaining healthy adipose tissue [33, 34]. Overall, these data suggest that multiple cell types produce depot-specific ECM and contribute to adipose tissue fibrosis.

Function of ECM in Adipose Tissue Fibrosis

Adipocytes are mechanically and structurally supported by the ECM (several collagen, laminin, fibronectin, and proteoglycan molecules), and interactions among these components maintain the ECM physiology through extensive signaling events [35, 36]. It is well-established that the protein content of the ECM in adipose tissue is similar to that of other tissues, although the relative and molecular quantities and assembly of ECM proteins in the adipose tissue differ from those in other organs and tissues [37]. Collagens, laminins, and fibronectin are highly expressed components of subcutaneous adipose tissue [35]. Notably, expression profile analysis revealed that collagens I, III, V, and VI are increased in subjects with obesity [8, 38, 39]. Among the collagens, type VI is the dominant form necessary for sustaining the structure and function of adipose tissue [37, 39-41]. Particularly, mature collagen VI is highly expressed in visceral adipose tissue, and its expression increases with obesity [42]. In addition, Col6-deficient mice reportedly exhibit lower tissue fibrosis and inflammation in WAT, while showing improved glucose tolerance, insulin sensitivity, and greater fatty acid consumption [40]. These results were confirmed in a study of C-terminal cleavage products focusing on the C5 domain of collagen VI α3 (endotrophin). Blocking endotrophin signaling with a neutralizing antibody ameliorated metabolic dysfunction and its adverse effects [43]. Thus, blocking fiber production in adipose tissue may improve obesity-related metabolic disorders.

Adipose tissue fibrosis is dynamically regulated and maintained by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases [44-47]. Among the 28 members of the MMP superfamily, MMP-3, -9, -11, -12, -13, -14, -16, and -24 are highly expressed and modulated under different physiological conditions in adipose tissue [48-50]. A series of studies targeting MMP genes were performed to examine the functions of each MMP in obesity and insulin resistance but the results have not been entirely consistent [51-53].

MMP14, also known as membrane-bound type 1-MMP (MT1-MMP), is the predominant pericellular collagenase involved in collagen I degradation in adipose tissue [54]. Furthermore, MMP14, which is induced by hypoxia-inducible factor 1α (HIF1α), mechanistically digests collagen 6α3 [55]. Genetic ablation of MMP14 leads to dysregulated collagen deposition and subsequent development of severe metabolic disorders [54]. In contrast, overexpression of MMP14 in adipose tissue with established obesity stimulates local fibrosis and inflammation [55].

Multiple factors contribute to adipose tissue fibrosis associated with obesity progression, as summarized in Fig. 2. ECM synthesis by myofibroblasts is a crucial step in adipose tissue expansion. The mechanical interaction between adipocytes and the ECM may serve as a target for treating adipocyte dysfunction and metabolic diseases [50].

Fig. 2

Schematic understanding of obesity-associated adipose tissue fibrosis

A complex interplay occurs among adipocytes, myofibroblasts, and immune cells during the progression of adipose tissue fibrosis.

Transcriptional Regulation of Adipose Tissue Fibrosis

Brown and beige adipocytes are regulated by epigenetics and several transcriptional regulators [56]. Brown adipocytes arise from Myf5⁺ dermatomal precursors through the transcriptional action of PR domain containing protein16 (PRDM16), which plays crucial roles in brown/beige adipogenesis and maintenance of cell fate [57, 58]. In fact, our research group recently identified a cold-inducible transcriptional factor, named “general transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1)”, as a member of the transcription factor II-I family of DNA-binding proteins. GTF2IRD1 forms a transcriptional complex with PRDM16 and euchromatic histone lysine methyltransferase 1 (EHMT1). GTF2IRD1 inhibits several fibrosis-related gene expressions through the PRDM16-EHMT1-GTF2IRD1 transcriptional complex, thereby improving systemic glucose homeostasis [10]. Interestingly, this transcription factor initially suppresses several genes encoding pro-fibrosis proteins such as collagens, MMPs, and galectins, suggesting its involvement in fibrosis development. In addition, hydroxybutyrate derived from PRDM16-expressing adipocytes may reduce fibrogenic activities and enhance beige adipogenesis [11]. Although it is not considered as a target for slowing or reversing adipose tissue fibrosis, this transcription factor may serve as a target for inhibiting fibrosis deposition.

Adipokines and Fibrosis

Adipose tissue is recognized as an endocrine organ capable of secreting a vast array of cytokines, known as adipokines, that control whole-body energy homeostasis [59]. The adipokine profile changes dynamically in response to nutritional stimuli [59]. To date, several adipose tissue-derived secretory products have been identified and their functions have been studied [60]. Among these numerous adipokines, adiponectin and leptin are the most intensively studied, given their effects on the expansion of healthy adipose tissue [61-63]. Adiponectin, a key adipokine involved in energy homeostasis, exhibits anti-inflammatory properties. Adiponectin acts on macrophages, inhibits the development of foam cells, and decreases endothelial cell activation and monocyte adhesion, resulting in the marked polarization of M2-like macrophages [64]. Leptin is another important adipokine involved in fibrosis in multiple peripheral organs [65, 66]. To date, studies have shown that leptin activates the expression of PRDM16 through its downstream Janus kinase 2-signal transducer and activator of transcription signaling pathway, thereby promoting browning of white adipose tissue [67].

During obesity progression, pro-inflammatory adipokines, such as tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1, and resistin, are highly expressed and secreted, contributing to the activation of a chronic inflammatory state and the recruitment of pro-inflammatory immune cells [68, 69].

Other adipokines that regulate ECM remodeling in adipose tissue have been identified [70-74]. Specifically, C-X-C motif chemokine ligand 14 (CXCL14) is secreted from brown adipose tissue in response to thermogenic activation [75]. CXCL14 promotes the browning of WAT through the activation of type 2 immune cells. These findings suggest that CXCL14 plays a pivotal role in adiposity and related metabolic disorders. Interestingly, serum CXCL14 levels were reported to be associated with the fatty liver index and serum C-peptide levels in patients with type 2 diabetes [76].

Hypoxia

WAT is a highly dynamic and heterogeneous organ. The expansion of WAT requires coordinated adaptations to maintain its microenvironment healthy. Substantial evidence has indicated that the oxygen tension is low and the expression of the master regulator hypoxia inducible factor (HIF)-1α is increased in the WAT from obese subjects [19, 77]. HIF-1α, in turn, induces the expression of several fibrotic proteins including various collagens, elastin, lysyl oxidase, and connective tissue growth factor [78-80]. Vascular endothelial growth factor (VEGF)-A regulates blood vessel permeability and growth. Additionally, VEGF-A and VEGF-B balance the energy homeostasis in the WAT [81]. Using a doxycycline-regulated VEGF-A suppression mouse model, Lu et al. found that suppression of VEGF-A leads to increased thermogenic activity in the WAT and resistance to high-fat diet-induced obesity [82]. Interestingly, in two genetic models, VEGF-A overexpression produced a rapid beigeing phenotype in the WAT and increased the number of M2 anti-inflammatory macrophages with improved insulin sensitivity [83].

Inflammation

Inflammation and fibrosis in adipose tissue have an extremely complex relationship [84, 85]. The mechanisms underlying fibrosis are fundamentally similar to the tissue damage characteristics of the normal wound healing response. These responses entail an activation of local immune cells, followed by the activation of local mesenchymal cells and fibroblasts, resulting in the deposition of excessive and/or inappropriate ECM components. These actions further increase the production of pro-inflammatory cytokines and chemokines, which are angiogenic factors [86, 87]. Visceral WAT in the setting of obesity is characterized by chronic, low-grade inflammation, which is regarded as both a cause and consequence of immune responses [84, 85, 88, 89]. The function of obese adipose tissue macrophages, which can be resident or recruited, can be used to predict metabolic dysfunction [90]. Macrophages are classified according to their cell surface markers and secretory profile as M1, referred to as “classically activated”, and M2, also known as “alternatively activated” [91]. They can also be classified into two highly different profiles, with opposite actions: “pro-inflammatory (M1)” and “anti-inflammatory (M2)”. M1 macrophages play key roles in initiating and sustaining inflammatory responses, secreting pro-inflammatory cytokines, and recruiting other immune cells. In contrast, M2 macrophages resolve inflammation, coordinate tissue injury, release anti-inflammatory mediators, and promote repair [92]. In addition, Foxp3⁺ CD4⁺ regulatory T cells are abundant in the visceral adipose tissue of lean subjects, whereas their number is greatly reduced in obese subjects [93]. Obesity also induces another important immune response involving other adaptive immune cells (B and T lymphocytes, e.g., CD8⁺ effector T cells) [94-96] as well as innate immune cells (neutrophils, dendritic cells, mast cells or eosinophils, and innate lymphoid cells type 2) [97-101]. A unique feature of obese adipose tissue is a crown-like structure (CLS), a histological hallmark of the inflammatory response. This CLS indicates a dying or dead adipocyte surrounded by macrophages [84, 85, 102]. Macrophage-inducible C-type lectin (MINCLE) is induced in macrophages constituting CLS through Toll-like receptor 4 signaling [103, 104]. MINCLE-deficient mice are protected against obesity-induced CLS formation and adipose tissue fibrosis [105]. Furthermore, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key sensor that functions in the innate immune system and is the predominant determinant of metabolic disorders [106, 107]. Blockade of NLRP3 inflammasome reduces adipose tissue inflammation and significantly attenuates fibrosis [108].

Crosstalk between adipocytes and endothelial cells potentially regulates systemic energy homeostasis in metabolic disorders [109]. Blockade of endothelial nuclear factor-kappa B signaling prevents obesity-induced inflammation, insulin resistance, and adipose tissue remodeling [110]. These complex interactions regulate systemic metabolism and insulin sensitivity [111].

Clinical Manifestations Related to Adipose Tissue Fibrosis

It is now established that obesity induces WAT inflammation and fibrosis, leading to local and systemic insulin resistance, which results in metabolic dysfunction in rodents. However, studies in humans showed conflicting correlations between adipose tissue fibrosis and metabolic disorders [8, 112-114]. Adipose tissue fibrosis in the context of human obesity differs between people with and without diabetes [115]. In addition, the ECM itself regulates adipocyte metabolism and function, both of which are affected by diabetes mellitus [116]. However, contradictory evidence has been reported, that is, decreased adipose tissue fibrosis was observed in obese people with diabetes [112]. Adipose tissue fibrosis has both adaptive and maladaptive functions. Thus, the functional consequences of adipose tissue fibrosis remain a matter of debate, and patient demographics and blood glucose history should be considered when evaluating these consequences.

Correlations with NAFLD and Metabolic Surgery

Hypertrophic WAT is associated with limited lipid storage capacity, resulting in ectopic fat accumulation in the liver, pancreas, heart, and kidneys, as well as the skeletal and cardiac muscles, thereby exacerbating insulin resistance [117]. Ectopic lipid deposition in the liver is highly associated with nonalcoholic fatty liver disease (NAFLD) and liver fibrosis, which are associated with macrophage infiltration in the visceral adipose tissue and the degree of fibrosis in subcutaneous adipose tissue [118, 119].

Weight reduction after metabolic surgery leads to dramatic improvements in metabolic, hepatic, and cardiovascular complications, as well as alterations in the WAT, such as inflammation, changes in insulin sensitivity, and abnormalities in numerous metabolic pathways [120]. Human omental WAT fibrosis is closely related to the degree of insulin resistance in severe obesity [121]. Among the approaches used to evaluate adipose tissue fibrosis, subcutaneous WAT stiffness, measured through noninvasive vibration-controlled transient elastography, called fibrosis score of adipose tissue (FAT score), has been proposed. This obtained value reflects fibrosis and correlates negatively with the body mass index and metabolic parameters (glucose, insulin, and lipid values) [114]. In addition, the FAT score, which reflects adipose tissue fibrosis, may facilitate the prediction of weight loss outcomes in patients undergoing metabolic surgery [122].

However, the impact of metabolic surgery on MMPs remains controversial. In patients with morbid obesity, serum MMP-2 and MMP-9 levels decrease significantly after surgery [123]. MMP-2 and MMP-9 activities were increased in obese patients without diabetes. In contrast, in obese patients with diabetes, there were no differences in MMP-2 and MMP-9 activities, and serum levels of MMP-7 were unchanged postoperatively [124, 125].

These observations support the “adipose tissue expandability hypothesis” [126], which states that increased WAT stiffness represents a mechanical limitation of WAT expansion. When the storage capacity of subcutaneous WAT reaches its limit, excess lipids shift to ectopic sites, such as the liver, heart, muscle, and pancreas, thereby causing and exacerbating metabolic complications [127, 128].

Summary and Future Perspectives

This review highlighted the biology of adipose tissue fibrosis, focusing on the complex interplay among adipocytes, non-adipocytes, ECM components, and associated mediators in obesity. This interplay, involving adipocytes, progenitors, inflammatory blood cells, and vascular endothelial cells, determines the remodeling conditions in the ECM and impacts the overall metabolic health of individuals. Inducers of browning/beigeing adipocytes and adipokines, as well as modulations of matrix remodeling enzymes, inhibitors, and associated gene regulators, are potential pharmacological targets for treating metabolic disorders such as obesity. The influence of adipose tissue fibrosis and its components on metabolic dysfunction is not completely understood. Further studies are thus needed to explore the pathogenesis and mechanisms of adipose tissue fibrosis, which is essential for alleviating metabolic disorders.

Acknowledgements

The author wishes to thank Prof. Yasushi Ishigaki and Prof. Shingo Kajimura for their ongoing support. This work was also supported by JSPS KAKENHI Grant Number JP17K08667.

Conflict of Interest Disclosure

The author has no competing interests to disclose.

References

• 1   Bluher  M (2019) Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol 15: 288–298.
• 2   Jo  J,  Gavrilova  O,  Pack  S,  Jou  W,  Mullen  S, et al. (2009) Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput Biol 5: e1000324.
• 3   Rutkowski  JM,  Stern  JH,  Scherer  PE (2015) The cell biology of fat expansion. J Cell Biol 208: 501–512.
• 4   Shook  B,  Rodeheffer  MS (2017) Forecasting fat fibrosis. Cell Metab 25: 493–494.
• 5   Crewe  C,  An  YA,  Scherer  PE (2017) The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest 127: 74–82.
• 6   Chouchani  ET,  Kajimura  S (2019) Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 1: 189–200.
• 7   Dankel  SN,  Svard  J,  Mattha  S,  Claussnitzer  M,  Kloting  N, et al. (2014) COL6A3 expression in adipocytes associates with insulin resistance and depends on PPARgamma and adipocyte size. Obesity (Silver Spring) 22: 1807–1813.
• 8   Divoux  A,  Tordjman  J,  Lacasa  D,  Veyrie  N,  Hugol  D, et al. (2010) Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 59: 2817–2825.
• 9   Datta  R,  Podolsky  MJ,  Atabai  K (2018) Fat fibrosis: friend or foe? JCI Insight 3: e122289.
• 10   Hasegawa  Y,  Ikeda  K,  Chen  Y,  Alba  DL,  Stifler  D, et al. (2018) Repression of adipose tissue fibrosis through a PRDM16-GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab 27: 180–194.e6.
• 11   Wang  W,  Ishibashi  J,  Trefely  S,  Shao  M,  Cowan  AJ, et al. (2019) A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab 30: 174–189.e5.
• 12   Kajimura  S (2015) Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway. Int J Obes Suppl 5: S11–S14.
• 13   Kaisanlahti  A,  Glumoff  T (2019) Browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes. J Physiol Biochem 75: 1–10.
• 14   Altinova  AE (2022) Beige adipocyte as the flame of white adipose tissue: regulation of browning and impact of obesity. J Clin Endocrinol Metab 107: e1778–e1788.
• 15   Oguri  Y,  Shinoda  K,  Kim  H,  Alba  DL,  Bolus  WR, et al. (2020) CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 182: 563–577.e20.
• 16   Wu  L,  Xia  M,  Duan  Y,  Zhang  L,  Jiang  H, et al. (2019) Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans. Cell Death Dis 10: 468.
• 17   Okla  M,  Kim  J,  Koehler  K,  Chung  S (2017) Dietary factors promoting brown and beige fat development and thermogenesis. Adv Nutr 8: 473–483.
• 18   Ellulu  MS,  Patimah  I,  Khaza’ai  H,  Rahmat  A,  Abed  Y (2017) Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci 13: 851–863.
• 19   Trayhurn  P,  Alomar  SY (2015) Oxygen deprivation and the cellular response to hypoxia in adipocytes—perspectives on white and brown adipose tissues in obesity. Front Endocrinol (Lausanne) 6: 19.
• 20   Pardo  M,  Roca-Rivada  A,  Seoane  LM,  Casanueva  FF (2012) Obesidomics: contribution of adipose tissue secretome analysis to obesity research. Endocrine 41: 374–383.
• 21   Li  S,  Gao  H,  Hasegawa  Y,  Lu  X (2021) Fight against fibrosis in adipose tissue remodeling. Am J Physiol Endocrinol Metab 321: E169–E175.
• 22   Sengenes  C,  Lolmede  K,  Zakaroff-Girard  A,  Busse  R,  Bouloumie  A (2005) Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells. J Cell Physiol 205: 114–122.
• 23   Rodeheffer  MS,  Birsoy  K,  Friedman  JM (2008) Identification of white adipocyte progenitor cells in vivo. Cell 135: 240–249.
• 24   Berry  R,  Rodeheffer  MS (2013) Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol 15: 302–308.
• 25   Uezumi  A,  Fukada  S,  Yamamoto  N,  Takeda  S,  Tsuchida  K (2010) Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 12: 143–152.
• 26   Merrick  D,  Sakers  A,  Irgebay  Z,  Okada  C,  Calvert  C, et al. (2019) Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364: eaav2501.
• 27   Yang Loureiro  Z,  Solivan-Rivera  J,  Corvera  S (2022) Adipocyte heterogeneity underlying adipose tissue functions. Endocrinology 163: bqab138.
• 28   Marcelin  G,  Ferreira  A,  Liu  Y,  Atlan  M,  Aron-Wisnewsky  J, et al. (2017) A PDGFRalpha-mediated switch toward CD9(high) adipocyte progenitors controls obesity-induced adipose tissue fibrosis. Cell Metab 25: 673–685.
• 29   Marangoni  RG,  Korman  BD,  Wei  J,  Wood  TA,  Graham  LV, et al. (2015) Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol 67: 1062–1073.
• 30   Keophiphath  M,  Achard  V,  Henegar  C,  Rouault  C,  Clement  K, et al. (2009) Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol 23: 11–24.
• 31   McDonald  ME,  Li  C,  Bian  H,  Smith  BD,  Layne  MD, et al. (2015) Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell 160: 105–118.
• 32   Lin  JZ,  Rabhi  N,  Farmer  SR (2018) Myocardin-related transcription factor a promotes recruitment of ITGA5+ profibrotic progenitors during obesity-induced adipose tissue fibrosis. Cell Rep 23: 1977–1987.
• 33   Jeffery  E,  Wing  A,  Holtrup  B,  Sebo  Z,  Kaplan  JL, et al. (2016) The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab 24: 142–150.
• 34   Wang  QA,  Scherer  PE (2014) The AdipoChaser mouse: a model tracking adipogenesis in vivo. Adipocyte 3: 146–150.
• 35   Mori  S,  Kiuchi  S,  Ouchi  A,  Hase  T,  Murase  T (2014) Characteristic expression of extracellular matrix in subcutaneous adipose tissue development and adipogenesis; comparison with visceral adipose tissue. Int J Biol Sci 10: 825–833.
• 36   Pellegrinelli  V,  Heuvingh  J,  du Roure  O,  Rouault  C,  Devulder  A, et al. (2014) Human adipocyte function is impacted by mechanical cues. J Pathol 233: 183–195.
• 37   Mariman  EC,  Wang  P (2010) Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci 67: 1277–1292.
• 38   Spencer  M,  Unal  R,  Zhu  B,  Rasouli  N,  McGehee  RE Jr, et al. (2011) Adipose tissue extracellular matrix and vascular abnormalities in obesity and insulin resistance. J Clin Endocrinol Metab 96: E1990–E1998.
• 39   Spencer  M,  Yao-Borengasser  A,  Unal  R,  Rasouli  N,  Gurley  CM, et al. (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299: E1016–E1027.
• 40   Khan  T,  Muise  ES,  Iyengar  P,  Wang  ZV,  Chandalia  M, et al. (2009) Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 29: 1575–1591.
• 41   Sun  K,  Tordjman  J,  Clement  K,  Scherer  PE (2013) Fibrosis and adipose tissue dysfunction. Cell Metab 18: 470–477.
• 42   Pasarica  M,  Gowronska-Kozak  B,  Burk  D,  Remedios  I,  Hymel  D, et al. (2009) Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab 94: 5155–5162.
• 43   Sun  K,  Park  J,  Gupta  OT,  Holland  WL,  Auerbach  P, et al. (2014) Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat Commun 5: 3485.
• 44   Wu  Y,  Lee  MJ,  Ido  Y,  Fried  SK (2017) High-fat diet-induced obesity regulates MMP3 to modulate depot- and sex-dependent adipose expansion in C57BL/6J mice. Am J Physiol Endocrinol Metab 312: E58–E71.
• 45   Martinez-Santibanez  G,  Singer  K,  Cho  KW,  DelProposto  JL,  Mergian  T, et al. (2015) Obesity-induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP-12. Adipocyte 4: 264–272.
• 46   Jaworski  DM,  Sideleva  O,  Stradecki  HM,  Langlois  GD,  Habibovic  A, et al. (2011) Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice. Endocrinology 152: 1300–1313.
• 47   Sakamuri  SS,  Watts  R,  Takawale  A,  Wang  X,  Hernandez-Anzaldo  S, et al. (2017) Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption. Sci Rep 7: 6210.
• 48   Maquoi  E,  Munaut  C,  Colige  A,  Collen  D,  Lijnen  HR (2002) Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. Diabetes 51: 1093–1101.
• 49   Jaoude  J,  Koh  Y (2016) Matrix metalloproteinases in exercise and obesity. Vasc Health Risk Manag 12: 287–295.
• 50   Lin  D,  Chun  TH,  Kang  L (2016) Adipose extracellular matrix remodelling in obesity and insulin resistance. Biochem Pharmacol 119: 8–16.
• 51   Traurig  MT,  Permana  PA,  Nair  S,  Kobes  S,  Bogardus  C, et al. (2006) Differential expression of matrix metalloproteinase 3 (MMP3) in preadipocytes/stromal vascular cells from nonobese nondiabetic versus obese nondiabetic Pima Indians. Diabetes 55: 3160–3165.
• 52   Chun  TH,  Inoue  M,  Morisaki  H,  Yamanaka  I,  Miyamoto  Y, et al. (2010) Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes 59: 2484–2494.
• 53   Lijnen  HR,  Van Hoef  B,  Rodriguez  JA,  Paramo  JA (2009) Stromelysin-2 (MMP-10) deficiency does not affect adipose tissue formation in a mouse model of nutritionally induced obesity. Biochem Biophys Res Commun 389: 378–381.
• 54   Chun  TH,  Hotary  KB,  Sabeh  F,  Saltiel  AR,  Allen  ED, et al. (2006) A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell 125: 577–591.
• 55   Li  X,  Zhao  Y,  Chen  C,  Yang  L,  Lee  HH, et al. (2020) Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity. Mol Cell Biol 40: e00564-19.
• 56   Inagaki  T,  Sakai  J,  Kajimura  S (2016) Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17: 480–495.
• 57   Kajimura  S,  Seale  P,  Kubota  K,  Lunsford  E,  Frangioni  JV, et al. (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460: 1154–1158.
• 58   Ohno  H,  Shinoda  K,  Ohyama  K,  Sharp  LZ,  Kajimura  S (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504: 163–167.
• 59   Rodriguez  A,  Ezquerro  S,  Mendez-Gimenez  L,  Becerril  S,  Fruhbeck  G (2015) Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism. Am J Physiol Endocrinol Metab 309: E691–E714.
• 60   Bernardi  O,  Estienne  A,  Reverchon  M,  Bigot  Y,  Froment  P, et al. (2021) Adipokines in metabolic and reproductive functions in birds: an overview of current knowns and unknowns. Mol Cell Endocrinol 534: 111370.
• 61   Straub  LG,  Scherer  PE (2019) Metabolic messengers: adiponectin. Nat Metab 1: 334–339.
• 62   Stern  JH,  Rutkowski  JM,  Scherer  PE (2016) Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab 23: 770–784.
• 63   Friedman  J (2016) The long road to leptin. J Clin Invest 126: 4727–4734.
• 64   Ohashi  K,  Parker  JL,  Ouchi  N,  Higuchi  A,  Vita  JA, et al. (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285: 6153–6160.
• 65   Saxena  NK,  Anania  FA (2015) Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab 26: 153–161.
• 66   Wolf  G,  Ziyadeh  FN (2006) Leptin and renal fibrosis. Contrib Nephrol 151: 175–183.
• 67   Gan  L,  Liu  Z,  Feng  F,  Wu  T,  Luo  D, et al. (2018) Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice. Int J Obes (Lond) 42: 252–259.
• 68   Timper  K,  Denson  JL,  Steculorum  SM,  Heilinger  C,  Engstrom-Ruud  L, et al. (2017) IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep 19: 267–280.
• 69   Hotamisligil  GS,  Shargill  NS,  Spiegelman  BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87–91.
• 70   Unamuno  X,  Gomez-Ambrosi  J,  Ramirez  B,  Rodriguez  A,  Becerril  S, et al. (2020) Dermatopontin, a novel adipokine promoting adipose tissue extracellular matrix remodelling and inflammation in obesity. J Clin Med 9: 1069.
• 71   Gomez de Segura  I,  Ahechu  P,  Gomez-Ambrosi  J,  Rodriguez  A,  Ramirez  B, et al. (2021) Decreased levels of microfibril-associated glycoprotein (MAGP)-1 in patients with colon cancer and obesity are associated with changes in extracellular matrix remodelling. Int J Mol Sci 22: 8485.
• 72   Fruhbeck  G,  Gomez-Ambrosi  J,  Rodriguez  A,  Ramirez  B,  Valenti  V, et al. (2018) Novel protective role of kallistatin in obesity by limiting adipose tissue low grade inflammation and oxidative stress. Metabolism 87: 123–135.
• 73   Wang  PY,  Feng  JY,  Zhang  Z,  Chen  Y,  Qin  Z, et al. (2022) The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway. Acta Pharmacol Sin 43: 367–375.
• 74   Guzman-Ruiz  R,  Tercero-Alcazar  C,  Lopez-Alcala  J,  Sanchez-Ceinos  J,  Malagon  MM, et al. (2021) The potential role of the adipokine HMGB1 in obesity and insulin resistance. Novel effects on adipose tissue biology. Mol Cell Endocrinol 536: 111417.
• 75   Cereijo  R,  Gavalda-Navarro  A,  Cairo  M,  Quesada-Lopez  T,  Villarroya  J, et al. (2018) CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab 28: 750–763.e6.
• 76   Matsushita  Y,  Hasegawa  Y,  Takebe  N,  Onodera  K,  Shozushima  M, et al. (2021) Serum C-X-C motif chemokine ligand 14 levels are associated with serum C-peptide and fatty liver index in type 2 diabetes mellitus patients. J Diabetes Investig 12: 1042–1049.
• 77   Sun  K,  Halberg  N,  Khan  M,  Magalang  UJ,  Scherer  PE (2013) Selective inhibition of hypoxia-inducible factor 1alpha ameliorates adipose tissue dysfunction. Mol Cell Biol 33: 904–917.
• 78   Wang  B,  Wood  IS,  Trayhurn  P (2007) Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch 455: 479–492.
• 79   Lee  KY,  Gesta  S,  Boucher  J,  Wang  XL,  Kahn  CR (2011) The differential role of Hif1beta/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation. Cell Metab 14: 491–503.
• 80   Pastel  E,  Price  E,  Sjoholm  K,  McCulloch  LJ,  Rittig  N, et al. (2018) Lysyl oxidase and adipose tissue dysfunction. Metabolism 78: 118–127.
• 81   Jin  H,  Li  D,  Wang  X,  Jia  J,  Chen  Y, et al. (2018) VEGF and VEGFB play balancing roles in adipose differentiation, gene expression, and function. Endocrinology 159: 2036–2049.
• 82   Lu  X,  Ji  Y,  Zhang  L,  Zhang  Y,  Zhang  S, et al. (2012) Resistance to obesity by repression of VEGF gene expression through induction of brown-like adipocyte differentiation. Endocrinology 153: 3123–3132.
• 83   Elias  I,  Franckhauser  S,  Ferre  T,  Vila  L,  Tafuro  S, et al. (2012) Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes 61: 1801–1813.
• 84   Reilly  SM,  Saltiel  AR (2017) Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol 13: 633–643.
• 85   Engin  A (2017) The pathogenesis of obesity-associated adipose tissue inflammation. Adv Exp Med Biol 960: 221–245.
• 86   Ung  CY,  Onoufriadis  A,  Parsons  M,  McGrath  JA,  Shaw  TJ (2021) Metabolic perturbations in fibrosis disease. Int J Biochem Cell Biol 139: 106073.
• 87   Dalmas  E,  Venteclef  N,  Caer  C,  Poitou  C,  Cremer  I, et al. (2014) T cell-derived IL-22 amplifies IL-1beta-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes 63: 1966–1977.
• 88   Engin  AB (2017) Adipocyte-macrophage cross-talk in obesity. Adv Exp Med Biol 960: 327–343.
• 89   Lee  BC,  Lee  J (2014) Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 1842: 446–462.
• 90   Blaszczak  AM,  Jalilvand  A,  Hsueh  WA (2021) Adipocytes, innate immunity and obesity: a mini-review. Front Immunol 12: 650768.
• 91   Lumeng  CN,  Bodzin  JL,  Saltiel  AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175–184.
• 92   Fujisaka  S,  Usui  I,  Bukhari  A,  Ikutani  M,  Oya  T, et al. (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58: 2574–2582.
• 93   Becker  M,  Levings  MK,  Daniel  C (2017) Adipose-tissue regulatory T cells: critical players in adipose-immune crosstalk. Eur J Immunol 47: 1867–1874.
• 94   Bertola  A,  Ciucci  T,  Rousseau  D,  Bourlier  V,  Duffaut  C, et al. (2012) Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61: 2238–2247.
• 95   Wu  H,  Ghosh  S,  Perrard  XD,  Feng  L,  Garcia  GE, et al. (2007) T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115: 1029–1038.
• 96   Nishimura  S,  Manabe  I,  Nagasaki  M,  Eto  K,  Yamashita  H, et al. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914–920.
• 97   Elgazar-Carmon  V,  Rudich  A,  Hadad  N,  Levy  R (2008) Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 49: 1894–1903.
• 98   Shapiro  H,  Pecht  T,  Shaco-Levy  R,  Harman-Boehm  I,  Kirshtein  B, et al. (2013) Adipose tissue foam cells are present in human obesity. J Clin Endocrinol Metab 98: 1173–1181.
• 99   Wu  D,  Molofsky  AB,  Liang  HE,  Ricardo-Gonzalez  RR,  Jouihan  HA, et al. (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332: 243–247.
• 100   Divoux  A,  Moutel  S,  Poitou  C,  Lacasa  D,  Veyrie  N, et al. (2012) Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab 97: E1677–E1685.
• 101   Mikhailova  SV,  Ivanoshchuk  DE (2021) Innate-immunity genes in obesity. J Pers Med 11: 1201.
• 102   Cinti  S,  Mitchell  G,  Barbatelli  G,  Murano  I,  Ceresi  E, et al. (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46: 2347–2355.
• 103   Vila  IK,  Badin  PM,  Marques  MA,  Monbrun  L,  Lefort  C, et al. (2014) Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. Cell Rep 7: 1116–1129.
• 104   Ichioka  M,  Suganami  T,  Tsuda  N,  Shirakawa  I,  Hirata  Y, et al. (2011) Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans. Diabetes 60: 819–826.
• 105   Tanaka  M,  Ikeda  K,  Suganami  T,  Komiya  C,  Ochi  K, et al. (2014) Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat Commun 5: 4982.
• 106   Vandanmagsar  B,  Youm  YH,  Ravussin  A,  Galgani  JE,  Stadler  K, et al. (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17: 179–188.
• 107   Youm  YH,  Grant  RW,  McCabe  LR,  Albarado  DC,  Nguyen  KY, et al. (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18: 519–532.
• 108   Unamuno  X,  Gomez-Ambrosi  J,  Ramirez  B,  Rodriguez  A,  Becerril  S, et al. (2021) NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling. Cell Mol Immunol 18: 1045–1057.
• 109   Sabaratnam  R,  Svenningsen  P (2021) Adipocyte-endothelium crosstalk in obesity. Front Endocrinol (Lausanne) 12: 681290.
• 110   Hasegawa  Y,  Saito  T,  Ogihara  T,  Ishigaki  Y,  Yamada  T, et al. (2012) Blockade of the nuclear factor-kappaB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation 125: 1122–1133.
• 111   Liao  ZZ,  Ran  L,  Qi  XY,  Wang  YD,  Wang  YY, et al. (2022) Adipose endothelial cells mastering adipose tissues metabolic fate. Adipocyte 11: 108–119.
• 112   Muir  LA,  Neeley  CK,  Meyer  KA,  Baker  NA,  Brosius  AM, et al. (2016) Adipose tissue fibrosis, hypertrophy, and hyperplasia: correlations with diabetes in human obesity. Obesity (Silver Spring) 24: 597–605.
• 113   Lackey  DE,  Burk  DH,  Ali  MR,  Mostaedi  R,  Smith  WH, et al. (2014) Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. Am J Physiol Endocrinol Metab 306: E233–E246.
• 114   Abdennour  M,  Reggio  S,  Le Naour  G,  Liu  Y,  Poitou  C, et al. (2014) Association of adipose tissue and liver fibrosis with tissue stiffness in morbid obesity: links with diabetes and BMI loss after gastric bypass. J Clin Endocrinol Metab 99: 898–907.
• 115   Henninger  AM,  Eliasson  B,  Jenndahl  LE,  Hammarstedt  A (2014) Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes. PLoS One 9: e105262.
• 116   Baker  NA,  Muir  LA,  Washabaugh  AR,  Neeley  CK,  Chen  SY, et al. (2017) Diabetes-specific regulation of adipocyte metabolism by the adipose tissue extracellular matrix. J Clin Endocrinol Metab 102: 1032–1043.
• 117   Murai  T,  Takebe  N,  Nagasawa  K,  Todate  Y,  Nakagawa  R, et al. (2017) Association of epicardial adipose tissue with serum level of cystatin C in type 2 diabetes. PLoS One 12: e0184723.
• 118   Tordjman  J,  Poitou  C,  Hugol  D,  Bouillot  JL,  Basdevant  A, et al. (2009) Association between omental adipose tissue macrophages and liver histopathology in morbid obesity: influence of glycemic status. J Hepatol 51: 354–362.
• 119   Beals  JW,  Smith  GI,  Shankaran  M,  Fuchs  A,  Schweitzer  GG, et al. (2021) Increased adipose tissue fibrogenesis, not impaired expandability, is associated with nonalcoholic fatty liver disease. Hepatology 74: 1287–1299.
• 120   Eriksson Hogling  D,  Ryden  M,  Backdahl  J,  Thorell  A,  Arner  P, et al. (2018) Body fat mass and distribution as predictors of metabolic outcome and weight loss after Roux-en-Y gastric bypass. Surg Obes Relat Dis 14: 936–942.
• 121   Guglielmi  V,  Cardellini  M,  Cinti  F,  Corgosinho  F,  Cardolini  I, et al. (2015) Omental adipose tissue fibrosis and insulin resistance in severe obesity. Nutr Diabetes 5: e175.
• 122   Bel Lassen  P,  Charlotte  F,  Liu  Y,  Bedossa  P,  Le Naour  G, et al. (2017) The FAT score, a fibrosis score of adipose tissue: predicting weight-loss outcome after gastric bypass. J Clin Endocrinol Metab 102: 2443–2453.
• 123   Domienik-Karlowicz  J,  Rymarczyk  Z,  Dzikowska-Diduch  O,  Lisik  W,  Chmura  A, et al. (2015) Emerging markers of atherosclerosis before and after bariatric surgery. Obes Surg 25: 486–493.
• 124   Yang  PJ,  Ser  KH,  Lin  MT,  Nien  HC,  Chen  CN, et al. (2015) Diabetes associated markers after bariatric surgery: fetuin-A, but not matrix metalloproteinase-7, is reduced. Obes Surg 25: 2328–2334.
• 125   Liu  Y,  Aron-Wisnewsky  J,  Marcelin  G,  Genser  L,  Le Naour  G, et al. (2016) Accumulation and changes in composition of collagens in subcutaneous adipose tissue after bariatric surgery. J Clin Endocrinol Metab 101: 293–304.
• 126   Virtue  S,  Vidal-Puig  A (2010) Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim Biophys Acta 1801: 338–349.
• 127   Carobbio  S,  Pellegrinelli  V,  Vidal-Puig  A (2017) Adipose tissue function and expandability as determinants of lipotoxicity and the metabolic syndrome. Adv Exp Med Biol 960: 161–196.
• 128   Gruzdeva  O,  Borodkina  D,  Uchasova  E,  Dyleva  Y,  Barbarash  O (2018) Localization of fat depots and cardiovascular risk. Lipids Health Dis 17: 218.