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Thematic Review Series| Volume 60, ISSUE 10, P1648-1697, October 2019

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

Open AccessPublished:June 17, 2019DOI:https://doi.org/10.1194/jlr.R094060
Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
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      The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.

      THE ENDOCRINE ERA OF ADIPOSE TISSUE

      The roles of white adipose tissue (WAT) in long-term energy storage, thermal insulation, and mechanical protection and of brown adipose tissue (BAT) in nonshivering thermogenesis have long been appreciated (
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      ). The lowering of circulating leptin levels due to a reduction in adipose tissue mass triggers behavioral, metabolic, and endocrine responses that aim at replenishing and preserving the body's fuel reserves (
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      ).
      Adiponectin, originally described in 1995 as “Acrp30” with additional reports following in 1996, is a protein exclusively produced by mature adipocytes (
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      ). It forms low molecular weight trimers, intermediate molecular weight hexamers, and high molecular weight dodeca- to octadecamers (
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      ). It signals through adiponectin receptor (AdipoR)1 and AdipoR2 and binds to the nonsignaling interacting protein, T-cadherin (
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      ). It is found in circulation and critically involved in many signaling events from the adipocyte to other cell types and tissues (
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      A novel serum protein similar to C1q, produced exclusively in adipocytes.
      J. Biol. Chem. 1995; 270: 26746-26749
      ). Its circulating levels are closely tied to the functional integrity of adipose tissue and decline with obesity (
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      ). It acts on the liver to decrease gluconeogenesis, on skeletal muscle to increase fatty acid oxidation, and on pancreatic β-cells and cardiac muscle cells as a key anti-lipotoxic agent, exerting many of these functions on the basis of its effects on sphingolipids (
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      ).
      Adiponectin and leptin are clearly the two most widely studied adipocyte-derived factors with nearly 50,000 combined citations in PubMed identified with the name of these two adipokines as key search terms. Many reviews cover them extensively, so we do not want to belabor these two adipokines in detail here. However, suffice it to say that much still remains to be learned about both of these factors. While they are unquestionably important, their detailed mechanisms of action at the level of their target cells and organs, the underlying systemic resistance to the effects of these hormones, and their mutual effects on each other are yet to be better understood.

      ADIPOSE TISSUE-SECRETED SIGNALING MEDIATORS

      Screening endeavors undertaken in the wake of the discovery of leptin and adiponectin have revealed a vast spectrum of adipose tissue-secreted signaling mediators (see Fig. 1 and Table 1 for a compilation of central factors, some of which are portrayed in detail below) (
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      ). The large diversity of adipose tissue secretory products may partially stem from the complex cellular composition of the tissue, which includes lipid-laden adipocytes, adipose tissue stromal cell populations of different adipogenic potentials, various immune cell populations, endothelial cells, pericytes, and neurons (
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      ). While the term “adipokine” is commonly used to refer to adipose tissue-derived proteins exclusively, it has occasionally been used to refer to the entirety of signaling mediators secreted by adipose tissue, and it is this latter definition that will be applied here.
      Figure thumbnail gr1
      Fig. 1Adipose tissue is a highly dynamic secretory organ that employs a plethora of adipokines (proteins, lipids, metabolites), noncoding RNAs, and EVs to relay information to other organs of the body.
      TABLE 1Collection of various adipose tissue-derived proteins, lipids, and metabolites with information on essential characteristics and several references for further reading
      ClassName (Abbreviation)CharacteristicsReferences
      ProteinsAngiotensin II (AII)Extracellular, generated(
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      Structure and functions of angiotensinogen.
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      Regulation and functions of the renin-angiotensin system in white and brown adipose tissue.
      Compr. Physiol. 2017; 7: 1137-1150
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      The link between adipose tissue renin-angiotensin-aldosterone system signaling and obesity-associated hypertension.
      Physiology (Bethesda). 2017; 32: 197-209
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      Central angiotensin II has catabolic action at white and brown adipose tissue.
      Am. J. Physiol. Endocrinol. Metab. 2011; 301: E1081-E1091
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      Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice.
      Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012; 302: R244-R251
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      Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity.
      J. Neurosci. 2013; 33: 4825-4833
      ,
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      Control of adipogenesis by the autocrine interplays between angiotensin 1–7/Mas receptor and angiotensin II/AT1 receptor signaling pathways.
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      ,
      • Palominos M.M.
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      Angiotensin II directly impairs adipogenic differentiation of human preadipose cells.
      Mol. Cell. Biochem. 2015; 408: 115-122
      ,
      • Palominos M.M.
      • Dunner N.H.
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      • Rojas C.V.
      Angiotensin II directly impairs adipogenic differentiation of human preadipose cells.
      Mol. Cell. Biochem. 2015; 408: 115-122
      ,
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      Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet.
      Adipocyte. 2015; 5: 43-52
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      ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity.
      Diabetes. 2016; 65: 85-95
      ,
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      Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.
      PLoS One. 2017; 12: e0180712
      ,
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      AT1 receptor antagonist induces thermogenic beige adipocytes in the inguinal white adipose tissue of obese mice.
      Endocrine. 2017; 55: 786-798
      ,
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      AT1 receptor antagonist induces thermogenic beige adipocytes in the inguinal white adipose tissue of obese mice.
      Endocrine. 2017; 55: 786-798
      ,
      • Than A.
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      Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis.
      Signal Transduct. Target. Ther. 2017; 2: 17022
      ,
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      Chronic administration of the angiotensin type 2 receptor agonist C21 improves insulin sensitivity in C57BL/6 mice.
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      )
      Generated from serine protease inhibitor A8/angiotensinogen (SERPINA8/AGT) by combined activity of renin or cathepsins and angiotensin-converting enzyme 1 (ACE1) or chymases
      Signals through G protein-coupled angiotensin receptor (ANGTR)1 and ANGTR2
      Regulates adipose tissue stromal cell adipogenesis
      Regulates adipose tissue thermogenesis
      Regulates blood pressure
      Regulates cardiac and vascular functions
      Regulates energy expenditure
      Regulates fluid homeostasis
      Regulates glucose tolerance and insulin sensitivity
      Regulates inflammation
      Regulates WAT browning
      May regulate body weight
      Increases adipocyte lipid uptake and lipogenesis
      Increases adipose tissue stromal cell proliferation
      Decreases adipocyte lipolysis
      ProteinsAdiponectin (ACRP30/ADIPOQ)Extracellular, secreted(
      • Straub L.G.
      • Scherer P.E.
      Metabolic messengers: adiponectin.
      Nature Metabolism. 2019; 1: 334-339
      ,
      • Wang Z.V.
      • Scherer P.E.
      Adiponectin, the past two decades.
      J. Mol. Cell Biol. 2016; 8: 93-100
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      • Berg A.H.
      • Pajvani U.B.
      • Scherer P.E.
      • Ahima R.S.
      Adiponectin acts in the brain to decrease body weight.
      Nat. Med. 2004; 10: 524-529
      ,
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      An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice.
      Cell Metab. 2013; 17: 790-797
      ,
      • Holland W.L.
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      • Halberg N.
      • Rutkowski J.M.
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      Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.
      Nat. Med. 2011; 17: 55-63
      ,
      • Bråkenhielm E.
      • Veitonmaki N.
      • Cao R.
      • Kihara S.
      • Matsuzawa Y.
      • Zhivotovsky B.
      • Funahashi T.
      • Cao Y.
      Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis.
      Proc. Natl. Acad. Sci. USA. 2004; 101: 2476-2481
      ,
      • Shibata R.
      • Ouchi N.
      • Kihara S.
      • Sato K.
      • Funahashi T.
      • Walsh K.
      Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling.
      J. Biol. Chem. 2004; 279: 28670-28674
      ,
      • Fu Y.
      • Luo N.
      • Klein R.L.
      • Garvey W.T.
      Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation.
      J. Lipid Res. 2005; 46: 1369-1379
      ,
      • Kim J.Y.
      • van de Wall E.
      • Laplante M.
      • Azzara A.
      • Trujillo M.E.
      • Hofmann S.M.
      • Schraw T.
      • Durand J.L.
      • Li H.
      • Li G.
      • et al.
      Obesity-associated improvements in metabolic profile through expansion of adipose tissue.
      J. Clin. Invest. 2007; 117: 2621-2637
      ,
      • Yamauchi T.
      • Nio Y.
      • Maki T.
      • Kobayashi M.
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      • Okada-Iwabu M.
      • Kawamoto S.
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      Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.
      Nat. Med. 2007; 13: 332-339
      ,
      • Okamoto M.
      • Ohara-Imaizumi M.
      • Kubota N.
      • Hashimoto S.
      • Eto K.
      • Kanno T.
      • Kubota T.
      • Wakui M.
      • Nagai R.
      • Noda M.
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      Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration.
      Diabetologia. 2008; 51: 827-835
      ,
      • Landskroner-Eiger S.
      • Qian B.
      • Muise E.S.
      • Nawrocki A.R.
      • Berger J.P.
      • Fine E.J.
      • Koba W.
      • Deng Y.
      • Pollard J.W.
      • Scherer P.E.
      Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo.
      Clin. Cancer Res. 2009; 15: 3265-3276
      ,
      • Miller R.A.
      • Chu Q.
      • Le Lay J.
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      • Ahima R.S.
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      • Viollet B.
      • Birnbaum M.J.
      Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling.
      J. Clin. Invest. 2011; 121: 2518-2528
      ,
      • Ye R.
      • Holland W.L.
      • Gordillo R.
      • Wang M.
      • Wang Q.A.
      • Shao M.
      • Morley T.S.
      • Gupta R.K.
      • Stahl A.
      • Scherer P.E.
      Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes beta-cell regeneration.
      eLife. 2014; 3
      doi:10.7554/eLife.03851
      )
      May be intracellular
      Signals through AdipoR1 and AdipoR2
      Binds T-cadherin
      Improves glucose tolerance and insulin sensitivity
      Maintains cardiac and vascular functions
      Regulates angiogenesis
      Regulates ceramide metabolism
      May regulate cancer growth and metastasis
      Increases adipocyte and skeletal muscle cell glucose uptake
      Increases adipocyte lipogenesis
      Increases adipose tissue stromal cell adipogenesis
      Increases β-cell survival
      Increases energy expenditure
      Increases hepatocyte and skeletal muscle cell fatty acid oxidation
      May increase β-cell glucose-stimulated insulin secretion
      Decreases adipose tissue stromal cell proliferation
      Decreases atherosclerosis
      Decreases hepatocyte lipogenesis
      Decreases inflammation
      Decreases liver gluconeogenesis
      Decreases liver steatosis
      ProteinsAngiopoietin 1 (ANG1)Extracellular, secreted(
      • Augustin H.G.
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      • Alitalo K.
      Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
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      Therapeutic targeting of the angiopoietin-TIE pathway.
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      Adipose tissue growth and regression are regulated by angiopoietin-1.
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      Signals through TIE2 and integrin αvβ5
      Improves glucose tolerance
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      Regulates cancer growth and metastasis
      Regulates inflammation
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      Increases angiogenesis
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      ProteinsAngiopoietin 2 (ANG2)Extracellular, secreted(
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      Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
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      Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels.
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      Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner.
      J. Clin. Invest. 2011; 121: 1624-1635
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      )
      Signals through TIE2, integrin α3β1, and integrin α5β1
      Improves glucose tolerance and lipid metabolism
      Regulates atherosclerosis
      Regulates cancer growth and metastasis
      Regulates inflammation
      Regulates vascular development and functions
      Increases angiogenesis
      Increases lymphangiogenesis
      Decreases fibrosis
      ProteinsAngiopoietin-like protein 2 (ANGPTL2)Intracellular and extracellular, secreted(
      • Kadomatsu T.
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      Diverse roles of ANGPTL2 in physiology and pathophysiology.
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      Molecular cloning, expression, and characterization of angiopoietin-related protein. angiopoietin-related protein induces endothelial cell sprouting.
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      Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane.
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      )
      Signals through LILRB2 and integrin α5β1
      Binds the G protein-coupled angiotensin receptor 1 (AGTR1) (intracellular)
      Furthers glucose intolerance and insulin resistance (chronic exposure)
      Regulates vascular functions
      Regulates hematopoiesis
      Increases atherosclerosis (chronic exposure)
      Increases cancer development, growth, and metastasis
      Increases inflammation
      Increases tissue integrity (acute exposure)
      Decreases tissue integrity (chronic exposure)
      ProteinsAngiopoietin-like protein 4 (ANGPTL4)Extracellular, secreted(
      • Zhang R.
      The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.
      Open Biol. 2016; 6: 150272
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      Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity.
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      The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure.
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      The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity.
      J. Biol. Chem. 2006; 281: 934-944
      )
      Inhibits LPL and pancreatic lipase
      Cleavage fragments may have signaling functions
      May further glucose intolerance and insulin resistance
      Regulates lipid trafficking
      May increase atherosclerosis
      May increase inflammation
      Decreases lipoprotein breakdown in adipose tissue during fasting
      ProteinsAngiopoietin-like protein 8 (ANGPTL8)Extracellular, secreted(
      • Zhang R.
      The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.
      Open Biol. 2016; 6: 150272
      ,
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      Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice.
      Proc. Natl. Acad. Sci. USA. 2018; 115: E1249-E1258
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      • Cohen J.C.
      • Hobbs H.H.
      Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.
      Proc. Natl. Acad. Sci. USA. 2013; 110: 16109-16114
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      • Alexa C.A.
      • Na E.
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      • Xin Y.
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      • Cohen J.C.
      • Hobbs H.H.
      • Murphy A.J.
      • Yancopoulos G.D.
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      ANGPTL8/betatrophin does not control pancreatic beta cell expansion.
      Cell. 2014; 159: 691-696
      )
      Acts in concert with ANGPTL3
      Inhibits LPL and endothelial lipase
      May further insulin resistance
      Regulates lipid trafficking
      Decreases lipoprotein breakdown in nonadipose tissues during feeding
      ProteinsApelin (APLN)Extracellular, secreted(
      • Castan-Laurell I.
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      • Kunduzova O.
      • Valet P.
      Apelin, a promising target for type 2 diabetes treatment?.
      Trends Endocrinol. Metab. 2012; 23: 234-241
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      The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis.
      J. Endocrinol. 2013; 219: R13-R35
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      Review: apelin in disease.
      Clin. Chim. Acta. 2018; 483: 241-248
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      Apelin stimulates glucose utilization in normal and obese insulin-resistant mice.
      Cell Metab. 2008; 8: 437-445
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      Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes.
      FASEB J. 2008; 22: 4146-4153
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      Apelin is necessary for the maintenance of insulin sensitivity.
      Am. J. Physiol. Endocrinol. Metab. 2010; 298: E59-E67
      ,
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      • Sun F.
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      Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3-L1 adipocytes.
      Mol. Cell. Biochem. 2011; 353: 305-313
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      Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice.
      Diabetes. 2012; 61: 310-320
      ,
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      Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways.
      Mol. Cell. Endocrinol. 2012; 362: 227-241
      ,
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      Apelin is a positive regulator of ACE2 in failing hearts.
      J. Clin. Invest. 2013; 123: 5203-5211
      ,
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      • Lu W.D.
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      Increased bone mass in mice lacking the adipokine apelin.
      Endocrinology. 2013; 154: 2069-2080
      ,
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      • Englander E.W.
      • Gomez G.A.
      • Rastellini C.
      • Quertermous T.
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      • Greeley Jr., G.H.
      Pancreatic islet APJ deletion reduces islet density and glucose tolerance in mice.
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      • He H.L.
      • Chua S.H.
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      Apelin enhances brown adipogenesis and browning of white adipocytes.
      J. Biol. Chem. 2015; 290: 14679-14691
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      Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.
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      • Geoffre N.
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      • Personnaz J.
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      Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism.
      Endocrine. 2018; 60: 112-121
      )
      Signals through G protein-coupled APLN receptor (APLNR)
      Improves glucose tolerance and insulin sensitivity
      Maintains cardiac functions
      Regulates fluid homeostasis
      May regulate bone mass
      Increases adipocyte and skeletal muscle cell glucose uptake
      Increases adipose tissue thermogenesis
      Increases angiogenesis
      Increases energy expenditure
      Increases lymphangiogenesis
      Increases skeletal muscle cell mitochondrial biogenesis and fatty acid oxidation
      Increases white adipocyte browning
      Decreases adipose tissue stromal cell adipogenesis
      Decreases blood pressure
      Decreases body weight
      May decrease adipocyte lipolysis
      May decrease inflammation
      May decrease liver steatosis
      ProteinsAutotaxin (ATX)Extracellular, secreted(
      • Ferry G.
      • Tellier E.
      • Try A.
      • Gres S.
      • Naime I.
      • Simon M.F.
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      Signals through ALK3 or ALK6 in complex with BMPR2, ACVR2a, or ACVR2b
      Maintains bone functions
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      May skew adipogenesis toward either white or brown phenotype
      Increases adipose tissue stromal cell adipogenesis
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      Signals through ALK4 in complex with ACVR2a or ACVR2b
      Improves glucose tolerance and insulin sensitivity
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      Increases activity
      Increases BAT activity
      Increases energy expenditure
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      Decreases adipose tissue stromal cell adipogenesis
      Decreases body weight gain
      May decrease bone mass
      ProteinsBone morphogenic protein 4 (BMP4)Extracellular, secreted(
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      Signals through ALK3 or ALK6 in complex with BMPR2, ACVR2a, or ACVR2b
      Improves glucose tolerance and insulin sensitivity
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      May regulate cancer development, growth, metastasis, and chemoresistance
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      Increase adipose tissue stromal cell adipogenesis
      Increases angiogenesis
      Increases BAT whitening
      Increases energy expenditure
      Increases food intake
      Increases WAT browning
      Increases WAT thermogenesis
      Decreases body weight gain
      Decreases brown adipocyte lipolysis
      Decreases BAT thermogenesis
      ProteinsBone morphogenic protein 8B (BMP8B)Extracellular, secreted(
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