The endocrine function of adipose tissues in health and cardiometabolic disease.
Journal
Nature reviews. Endocrinology
ISSN: 1759-5037
Titre abrégé: Nat Rev Endocrinol
Pays: England
ID NLM: 101500078
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
accepted:
17
06
2019
pubmed:
13
7
2019
medline:
27
2
2020
entrez:
13
7
2019
Statut:
ppublish
Résumé
In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease.
Identifiants
pubmed: 31296970
doi: 10.1038/s41574-019-0230-6
pii: 10.1038/s41574-019-0230-6
doi:
Substances chimiques
Adipokines
0
Hormones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
507-524Références
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
pubmed: 7984236
doi: 10.1038/372425a0
Karastergiou, K. & Mohamed-Ali, V. The autocrine and paracrine roles of adipokines. Mol. Cell Endocrinol. 318, 69–78 (2010).
pubmed: 19948207
doi: 10.1016/j.mce.2009.11.011
Lehr, S., Hartwig, S. & Sell, H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin. Appl. 6, 91–101 (2012).
pubmed: 22213627
doi: 10.1002/prca.201100052
Ali Khan, A. et al. Comparative secretome analyses of primary murine white and brown adipocytes reveal novel adipokines. Mol. Cell Proteomics 17, 2358–2370 (2018).
pubmed: 30135203
doi: 10.1074/mcp.RA118.000704
pmcid: 6283297
Seldin, M. M. et al. A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metab. 27, 1138–1155 (2018). This study identified lipocalin 5 as a novel adipokine regulating muscle mitochondria by using an unbiased computational approach based on multiorgan transcriptomics of various mouse strains.
pubmed: 29719227
pmcid: 5935137
doi: 10.1016/j.cmet.2018.03.015
Giordano, A., Smorlesi, A., Frontini, A., Barbatelli, G. & Cinti, S. White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ. Eur. J. Endocrinol. 170, R159–R171 (2014).
pubmed: 24468979
doi: 10.1530/EJE-13-0945
Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013).
pubmed: 23303913
doi: 10.1152/physrev.00033.2011
Scheja, L. & Heeren, J. Metabolic interplay between white, beige, brown adipocytes and the liver. J. Hepatol. 64, 1176–1186 (2016).
pubmed: 26829204
doi: 10.1016/j.jhep.2016.01.025
Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).
pubmed: 22307324
pmcid: 3287224
doi: 10.1172/JCI59701
Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).
pubmed: 28045400
pmcid: 5199684
doi: 10.1172/JCI88883
Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).
pubmed: 28045402
pmcid: 5199709
doi: 10.1172/JCI92035
Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).
doi: 10.1038/nature21363
pubmed: 28179656
Boucher, J., Kleinridders, A. & Kahn, C. R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6, a009191 (2014).
pubmed: 24384568
pmcid: 3941218
doi: 10.1101/cshperspect.a009191
Xu, X. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 18, 816–830 (2013).
pubmed: 24315368
pmcid: 3939841
doi: 10.1016/j.cmet.2013.11.001
Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).
pubmed: 30067154
doi: 10.1152/physrev.00063.2017
pmcid: 6170977
Kloting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).
pubmed: 20570822
doi: 10.1152/ajpendo.00586.2009
Karpe, F. & Pinnick, K. E. Biology of upper-body and lower-body adipose tissue—link to whole-body phenotypes. Nat. Rev. Endocrinol. 11, 90–100 (2015).
pubmed: 25365922
doi: 10.1038/nrendo.2014.185
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
pubmed: 14715917
doi: 10.1152/physrev.00015.2003
Li, Y. et al. Secretin-activated brown fat mediates prandial thermogenesis to induce satiation. Cell 175, 1561–1574 (2018).
pubmed: 30449620
doi: 10.1016/j.cell.2018.10.016
Heine, M. et al. Lipolysis triggers a systemic insulin response essential for efficient energy replenishment of activated brown adipose tissue in mice. Cell Metab. 28, 644–655 (2018).
pubmed: 30033199
doi: 10.1016/j.cmet.2018.06.020
Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).
pubmed: 24146030
doi: 10.1038/nrendo.2013.204
Villarroya, F., Cereijo, R., Villarroya, J., Gavalda-Navarro, A. & Giralt, M. Toward an understanding of how immune cells control brown and beige adipobiology. Cell Metab. 27, 954–961 (2018).
pubmed: 29719233
doi: 10.1016/j.cmet.2018.04.006
Takeshita, S., Fumoto, T., Naoe, Y. & Ikeda, K. Age-related marrow adipogenesis is linked to increased expression of RANKL. J. Biol. Chem. 289, 16699–16710 (2014).
pubmed: 24753250
pmcid: 4059115
doi: 10.1074/jbc.M114.547919
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
pubmed: 19516257
pmcid: 2831539
doi: 10.1038/nature08099
Cawthorn, W. P. et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 20, 368–375 (2014).
pubmed: 24998914
pmcid: 4126847
doi: 10.1016/j.cmet.2014.06.003
Costa, R. M., Neves, K. B., Tostes, R. C. & Lobato, N. S. Perivascular adipose tissue as a relevant fat depot for cardiovascular risk in obesity. Front. Physiol. 9, 253 (2018).
pubmed: 29618983
pmcid: 5871983
doi: 10.3389/fphys.2018.00253
Xiong, W. et al. Brown adipocyte-specific PPARγ (peroxisome proliferator-activated receptor gamma) deletion impairs perivascular adipose tissue development and enhances atherosclerosis in mice. Arterioscler Thromb. Vasc. Biol. 38, 1738–1747 (2018).
pubmed: 29954752
pmcid: 6202167
doi: 10.1161/ATVBAHA.118.311367
Antonopoulos, A. S. et al. Detecting human coronary inflammation by imaging perivascular fat. Sci. Transl Med. 9, eaal2658 (2017).
pubmed: 28701474
doi: 10.1126/scitranslmed.aal2658
Guglielmi, V. & Sbraccia, P. Epicardial adipose tissue: at the heart of the obesity complications. Acta Diabetol. 54, 805–812 (2017).
pubmed: 28664417
doi: 10.1007/s00592-017-1020-z
Bluher, M. & Mantzoros, C. S. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 64, 131–145 (2015).
pubmed: 25497344
doi: 10.1016/j.metabol.2014.10.016
Friedman, J. The long road to leptin. J. Clin. Invest. 126, 4727–4734 (2016).
pubmed: 27906690
pmcid: 5127673
doi: 10.1172/JCI91578
Fischer, A. W., Cannon, B. & Nedergaard, J. Leptin-deficient mice are not hypothermic, they are anapyrexic. Mol. Metab. 6, 173 (2017).
pubmed: 28180058
doi: 10.1016/j.molmet.2016.10.012
Farooqi, I. S. & O’Rahilly, S. 20 years of leptin: human disorders of leptin action. J. Endocrinol. 223, T63–70 (2014).
pubmed: 25232148
doi: 10.1530/JOE-14-0480
Boden, G., Chen, X., Mozzoli, M. & Ryan, I. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab. 81, 3419–3423 (1996).
pubmed: 8784108
Sinha, M. K. et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 97, 1344–1347 (1996).
pubmed: 8636448
pmcid: 507189
doi: 10.1172/JCI118551
Francisco, V. et al. Obesity, fat mass and immune system: role for leptin. Front. Physiol. 9, 640 (2018).
pubmed: 29910742
pmcid: 5992476
doi: 10.3389/fphys.2018.00640
Hube, F. et al. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm. Metab. Res. 28, 690–693 (1996).
pubmed: 9013743
doi: 10.1055/s-2007-979879
Wrann, C. D. et al. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J. Clin. Invest. 122, 1010–1021 (2012).
pubmed: 22326952
pmcid: 3322535
doi: 10.1172/JCI58431
Caron, A., Lee, S., Elmquist, J. K. & Gautron, L. Leptin and brain-adipose crosstalks. Nat. Rev. Neurosci. 19, 153–165 (2018).
pubmed: 29449715
pmcid: 5962962
doi: 10.1038/nrn.2018.7
Mantzoros, C. S. et al. Activation of β
pubmed: 8666142
doi: 10.2337/diab.45.7.909
Trayhurn, P., Duncan, J. S., Rayner, D. V. & Hardie, L. J. Rapid inhibition of ob gene expression and circulating leptin levels in lean mice by the beta 3-adrenoceptor agonists BRL 35135A and ZD2079. Biochem. Biophys. Res. Commun. 228, 605–610 (1996).
pubmed: 8920957
doi: 10.1006/bbrc.1996.1704
Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).
pubmed: 11602618
pmcid: 209535
doi: 10.1172/JCI200113914
Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).
pubmed: 26406372
doi: 10.1016/j.cell.2015.08.055
Hayes, M. R. et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11, 77–83 (2010).
pubmed: 20074530
pmcid: 2807619
doi: 10.1016/j.cmet.2009.10.009
Scott, M. M., Williams, K. W., Rossi, J., Lee, C. E. & Elmquist, J. K. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121, 2413–2421 (2011).
pubmed: 21606595
pmcid: 3104740
doi: 10.1172/JCI43703
Denroche, H. C. et al. Disrupted leptin signaling in the lateral hypothalamus and ventral premammillary nucleus alters insulin and glucagon secretion and protects against diet-induced obesity. Endocrinology 157, 2671–2685 (2016).
pubmed: 27183315
doi: 10.1210/en.2015-1998
Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).
pubmed: 29670283
pmcid: 5920723
doi: 10.1038/s41586-018-0049-7
Berglund, E. D. et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 122, 1000–1009 (2012).
pubmed: 22326958
pmcid: 3287225
doi: 10.1172/JCI59816
Hubert, A. et al. Selective deletion of leptin signaling in endothelial cells enhances neointima formation and phenocopies the vascular effects of diet-induced obesity in mice. Arterioscler. Thromb. Vasc. Biol. 37, 1683–1697 (2017). Using endothelial cell-specific Lepr -knockout mice, this study identified leptin signalling in endothelial cells as an important mechanism counteracting obesity-associated neointima formation.
pubmed: 28705795
doi: 10.1161/ATVBAHA.117.309798
Wu, Y., Fortin, D. A., Cochrane, V. A., Chen, P. C. & Shyng, S. L. NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic beta-cells. J. Biol. Chem. 292, 15512–15524 (2017).
pubmed: 28768770
pmcid: 5602408
doi: 10.1074/jbc.M117.802249
Dunmore, S. J. & Brown, J. E. The role of adipokines in beta-cell failure of type 2 diabetes. J. Endocrinol. 216, T37–45 (2013).
pubmed: 22991412
doi: 10.1530/JOE-12-0278
Soedling, H. et al. Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells. Mol. Metab. 4, 619–630 (2015).
pubmed: 26413468
pmcid: 4563029
doi: 10.1016/j.molmet.2015.06.007
Fang, H. & Judd, R. L. Adiponectin regulation and function. Compr. Physiol. 8, 1031–1063 (2018).
pubmed: 29978896
doi: 10.1002/cphy.c170046
Komai, A. M. et al. White adipocyte adiponectin exocytosis is stimulated via β3-adrenergic signaling and activation of Epac1: catecholamine resistance in obesity and type 2 diabetes. Diabetes 65, 3301–3313 (2016).
pubmed: 27554468
doi: 10.2337/db15-1597
Kikai, M. et al. Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE
pubmed: 29496444
doi: 10.1016/j.bbrc.2018.02.185
Trayhurn, P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93, 1–21 (2013).
pubmed: 23303904
doi: 10.1152/physrev.00017.2012
Sulston, R. J. et al. Increased circulating adiponectin in response to thiazolidinediones: investigating the role of bone marrow adipose tissue. Front. Endocrinol. 7, 128 (2016).
doi: 10.3389/fendo.2016.00128
Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737 (2002).
pubmed: 12068289
doi: 10.1038/nm724
Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).
pubmed: 17717599
pmcid: 1950456
doi: 10.1172/JCI31021
Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003).
pubmed: 12802337
doi: 10.1038/nature01705
Mao, X. et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat. Cell Biol. 8, 516–523 (2006).
pubmed: 16622416
doi: 10.1038/ncb1404
Vasiliauskaite-Brooks, I. et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544, 120–123 (2017).
pubmed: 28329765
pmcid: 5595237
doi: 10.1038/nature21714
Ye, R., Wang, M., Wang, Q. A. & Scherer, P. E. Adiponectin-mediated antilipotoxic effects in regenerating pancreatic islets. Endocrinology 56, 2019–2028 (2015).
doi: 10.1210/en.2015-1066
Mandal, P., Pratt, B. T., Barnes, M., McMullen, M. R. & Nagy, L. E. Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J. Biol. Chem. 286, 13460–13469 (2011).
pubmed: 21357416
pmcid: 3075692
doi: 10.1074/jbc.M110.204644
Caligiuri, A. et al. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 47, 668–676 (2008).
pubmed: 18098312
doi: 10.1002/hep.21995
Okamoto, Y. et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106, 2767–2770 (2002).
pubmed: 12451000
doi: 10.1161/01.CIR.0000042707.50032.19
Qiao, L. et al. Adiponectin deficiency impairs maternal metabolic adaptation to pregnancy in mice. Diabetes 66, 1126–1135 (2017).
pubmed: 28073830
pmcid: 5399613
doi: 10.2337/db16-1096
Cheng, L. et al. Adiponectin deficiency leads to female subfertility and ovarian dysfunctions in mice. Endocrinology 157, 4875–4887 (2016).
pubmed: 27700136
doi: 10.1210/en.2015-2080
Aye, I. L., Rosario, F. J., Powell, T. L. & Jansson, T. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc. Natl Acad. Sci. USA 112, 12858–12863 (2015).
pubmed: 26417088
doi: 10.1073/pnas.1515484112
pmcid: 4611638
Hu, X. et al. MitoNEET deficiency alleviates experimental alcoholic steatohepatitis in mice by stimulating endocrine adiponectin-Fgf15 axis. J. Biol. Chem. 291, 22482–22495 (2016).
pubmed: 27573244
pmcid: 5077187
doi: 10.1074/jbc.M116.737015
Wang, J. et al. Myeloid cell-specific lipin-1 deficiency stimulates endocrine adiponectin-FGF15 axis and ameliorates ethanol-induced liver injury in mice. Sci. Rep. 6, 34117 (2016).
pubmed: 27666676
pmcid: 5036185
doi: 10.1038/srep34117
Cook, K. S. et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237, 402–405 (1987).
pubmed: 3299705
doi: 10.1126/science.3299705
Wu, X. et al. Contribution of adipose-derived factor D/adipsin to complement alternative pathway activation: lessons from lipodystrophy. J. Immunol. 200, 2786–2797 (2018).
pubmed: 29531168
doi: 10.4049/jimmunol.1701668
Hertle, E. et al. The alternative complement pathway is longitudinally associated with adverse cardiovascular outcomes. The CODAM study. Thromb. Haemost. 115, 446–457 (2016).
pubmed: 26446431
doi: 10.1160/th15-05-0439
McCullough, R. L. et al. Complement factor D protects mice from ethanol-induced inflammation and liver injury. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G66–G79 (2018).
pubmed: 29597356
pmcid: 6109707
doi: 10.1152/ajpgi.00334.2017
Lo, J. C. et al. Adipsin is an adipokine that improves beta cell function in diabetes. Cell 158, 41–53 (2014).
pubmed: 24995977
pmcid: 4128197
doi: 10.1016/j.cell.2014.06.005
Maslowska, M. et al. Plasma acylation stimulating protein, adipsin and lipids in non-obese and obese populations. Eur. J. Clin. Invest. 29, 679–686 (1999).
pubmed: 10457151
doi: 10.1046/j.1365-2362.1999.00514.x
Hotamisligil, G. S. & Bernlohr, D. A. Metabolic functions of FABPs—mechanisms and therapeutic implications. Nat. Rev. Endocrinol. 11, 592–605 (2015).
pubmed: 26260145
pmcid: 4578711
doi: 10.1038/nrendo.2015.122
Villeneuve, J. et al. Unconventional secretion of FABP4 by endosomes and secretory lysosomes. J. Cell Biol. 217, 649–665 (2018).
pubmed: 29212659
pmcid: 5800802
doi: 10.1083/jcb.201705047
Cao, H. et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 17, 768–778 (2013).
pubmed: 23663740
pmcid: 3755450
doi: 10.1016/j.cmet.2013.04.012
Burak, M. F. et al. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Sci. Transl Med. 7, 319ra205 (2015).
pubmed: 26702093
doi: 10.1126/scitranslmed.aac6336
Girona, J. et al. FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway. PLOS ONE 8, e81914 (2013).
pubmed: 24312381
pmcid: 3843707
doi: 10.1371/journal.pone.0081914
Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014). This study discovered that cold exposure triggers the induction of NRG4 expression in BAT of mice and in parallel reduces hepatic DNL through NRG4 receptor (ERBB3/ERBB4) signalling, providing evidence for a novel endocrine BAT–liver axis.
pubmed: 25401691
pmcid: 4257907
doi: 10.1038/nm.3713
Guo, L. et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J. Clin. Invest. 127, 4449–4461 (2017).
pubmed: 29106384
pmcid: 5707158
doi: 10.1172/JCI96324
Nugroho, D. B., Ikeda, K., Kajimoto, K., Hirata, K. I. & Emoto, N. Activation of neuregulin-4 in adipocytes improves metabolic health by enhancing adipose tissue angiogenesis. Biochem. Biophys. Res. Commun. 504, 427–433 (2018).
pubmed: 30195497
doi: 10.1016/j.bbrc.2018.08.197
Nugroho, D. B. et al. Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature. Biochem. Biophys. Res. Commun. 503, 378–384 (2018).
pubmed: 29902456
doi: 10.1016/j.bbrc.2018.06.043
Christian, M. Transcriptional fingerprinting of “browning” white fat identifies NRG4 as a novel adipokine. Adipocyte 4, 50–54 (2015).
pubmed: 26167402
doi: 10.4161/adip.29853
Chen, Z. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol. Metab. 6, 863–872 (2017).
pubmed: 28752050
pmcid: 5518721
doi: 10.1016/j.molmet.2017.03.016
Montagner, A. et al. Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 1202–1214 (2016).
pubmed: 26838599
doi: 10.1136/gutjnl-2015-310798
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).
pubmed: 18805087
pmcid: 2728618
doi: 10.1016/j.cell.2008.07.048
Chan, K. L. et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J. Biol. Chem. 290, 16979–16988 (2015).
pubmed: 25987561
pmcid: 4505442
doi: 10.1074/jbc.M115.646992
Cimen, I. et al. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci. Transl Med. 8, 358ra126 (2016). The study showed that oral supplementation with the lipokine palmitoleate reduces the size of atherosclerotic lesions in apolipoprotein E-deficient mice by relieving cholesterol-induced endoplasmic reticulum stress and inflammatory mechanisms in macrophages.
pubmed: 27683551
doi: 10.1126/scitranslmed.aaf9087
Herman, M. A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).
pubmed: 22466288
pmcid: 3341994
doi: 10.1038/nature10986
Yang, Z. H., Miyahara, H. & Hatanaka, A. Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes. Lipids Health Dis. 10, 120 (2011).
pubmed: 21774832
pmcid: 3155149
doi: 10.1186/1476-511X-10-120
Guo, X. et al. Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice. PLOS ONE 7, e39286 (2012).
pubmed: 22768070
pmcid: 3387145
doi: 10.1371/journal.pone.0039286
Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat. Commun. 4, 1528 (2013).
pubmed: 23443556
doi: 10.1038/ncomms2537
Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014). This study describes the discovery of FAHFAs as a novel class of lipokines that are tightly linked to WAT DNL and systemic insulin sensitivity.
pubmed: 25303528
pmcid: 4260972
doi: 10.1016/j.cell.2014.09.035
Vijayakumar, A. et al. Absence of carbohydrate response element binding protein in adipocytes causes systemic insulin resistance and impairs glucose transport. Cell Rep. 21, 1021–1035 (2017).
pubmed: 29069585
pmcid: 5771491
doi: 10.1016/j.celrep.2017.09.091
Hammarstedt, A. et al. Adipose tissue dysfunction is associated with low levels of the novel palmitic acid hydroxystearic acids. Sci. Rep. 8, 15757 (2018).
pubmed: 30361530
pmcid: 6202399
doi: 10.1038/s41598-018-34113-3
Syed, I. et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27, 419–427 (2018).
pubmed: 29414687
pmcid: 5807007
doi: 10.1016/j.cmet.2018.01.001
Pflimlin, E. et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab. 28, 217–227 (2018).
pubmed: 29937376
doi: 10.1016/j.cmet.2018.05.028
Syed, I. et al. Methodological issues in studying PAHSA biology: masking PAHSA effects. Cell Metab. 28, 543–546 (2018).
pubmed: 30244974
pmcid: 6542592
doi: 10.1016/j.cmet.2018.09.007
Kuda, O. On the complexity of PAHSA research. Cell Metab. 28, 541–542 (2018).
pubmed: 30244970
doi: 10.1016/j.cmet.2018.09.006
Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017).
pubmed: 28346411
pmcid: 5699924
doi: 10.1038/nm.4297
Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120 (2018).
pubmed: 29719226
pmcid: 5935136
doi: 10.1016/j.cmet.2018.03.020
Huang-Doran, I., Zhang, C. Y. & Vidal-Puig, A. Extracellular vesicles: novel mediators of cell communication in metabolic disease. Trends Endocrinol. Metab. 28, 3–18 (2017).
pubmed: 27810172
doi: 10.1016/j.tem.2016.10.003
Chen, Y. et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat. Commun. 7, 11420 (2016).
pubmed: 27117818
pmcid: 4853423
doi: 10.1038/ncomms11420
Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).
pubmed: 28199304
pmcid: 5330251
doi: 10.1038/nature21365
Ying, W. et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171, 372–384 (2017).
pubmed: 28942920
doi: 10.1016/j.cell.2017.08.035
BonDurant, L. D. & Potthoff, M. J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 38, 173–196 (2018).
pubmed: 29727594
doi: 10.1146/annurev-nutr-071816-064800
pmcid: 6964258
Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).
pubmed: 26959184
doi: 10.1016/j.cmet.2016.02.001
Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016).
pubmed: 26853749
doi: 10.1016/j.cmet.2016.01.006
Hansen, J. S. et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol. Metab. 4, 551–560 (2015).
pubmed: 26266087
pmcid: 4529499
doi: 10.1016/j.molmet.2015.06.001
Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057–4063 (2014). This study identified the liver as the source of circulating FGF21 and its insulin-sensitizing effects in acute refeeding and overfeeding.
pubmed: 25008183
pmcid: 4238010
doi: 10.2337/db14-0595
Liang, Q. et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63, 4064–4075 (2014).
pubmed: 25024372
doi: 10.2337/db14-0541
BonDurant, L. D. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab. 25, 935–944 (2017).
pubmed: 28380381
pmcid: 5494834
doi: 10.1016/j.cmet.2017.03.005
Hondares, E. et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286, 12983–12990 (2011).
pubmed: 21317437
pmcid: 3075644
doi: 10.1074/jbc.M110.215889
Fisher, F. M. et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
pubmed: 22302939
pmcid: 3278894
doi: 10.1101/gad.177857.111
Huang, Z. et al. The FGF21-CCL11 axis mediates beiging of white adipose tissues by coupling sympathetic nervous system to type 2 immunity. Cell Metab. 26, 493–508 (2017).
pubmed: 28844880
doi: 10.1016/j.cmet.2017.08.003
Keipert, S. et al. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol. Metab. 4, 537–542 (2015).
pubmed: 26137441
pmcid: 4481421
doi: 10.1016/j.molmet.2015.04.006
Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).
pubmed: 23221344
doi: 10.1172/JCI62308
Ruan, C. C. et al. A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab. 28, 476–489 (2018). This study provides evidence that hypertension-induced cardiac hypertrophy and fibrosis is counter-regulated by FGF21 induced in and secreted by BAT in this condition.
pubmed: 30017353
doi: 10.1016/j.cmet.2018.06.013
Hjortebjerg, R. et al. Insulin, IGF-1, and GH receptors are altered in an adipose tissue depot-specific manner in male mice with modified GH action. Endocrinology 158, 1406–1418 (2017).
pubmed: 28323915
pmcid: 5460824
doi: 10.1210/en.2017-00084
Masternak, M. M. et al. Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice. Exp. Gerontol. 40, 679–684 (2005).
pubmed: 16054319
doi: 10.1016/j.exger.2005.06.003
Gunawardana, S. C. & Piston, D. W. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am. J. Physiol. Endocrinol. Metab. 308, E1043–E1055 (2015).
pubmed: 25898954
pmcid: 4469812
doi: 10.1152/ajpendo.00570.2014
Kloting, N. et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 6, 79–87 (2007).
pubmed: 17618858
doi: 10.1016/j.cmet.2007.06.002
Berry, D. C. et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye. J. Biol. Chem. 288, 24528–24539 (2013).
pubmed: 23839944
pmcid: 3750151
doi: 10.1074/jbc.M113.484014
Moraes-Vieira, P. M. et al. Antigen presentation and T-cell activation are critical for RBP4-induced insulin resistance. Diabetes 65, 1317–1327 (2016).
pubmed: 26936962
pmcid: 4839203
doi: 10.2337/db15-1696
Thompson, S. J. et al. Hepatocytes are the principal source of circulating RBP4 in mice. Diabetes 66, 58–63 (2017).
pubmed: 27797907
doi: 10.2337/db16-0286
Preitner, F., Mody, N., Graham, T. E., Peroni, O. D. & Kahn, B. B. Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 297, E1420–E1429 (2009).
pubmed: 19826103
pmcid: 2793052
doi: 10.1152/ajpendo.00362.2009
Fedders, R. et al. Liver-secreted RBP4 does not impair glucose homeostasis in mice. J. Biol. Chem. 293, 15269–15276 (2018).
pubmed: 30126844
doi: 10.1074/jbc.RA118.004294
pmcid: 6166712
Lee, S. A., Yuen, J. J., Jiang, H., Kahn, B. B. & Blaner, W. S. Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice. Hepatology 64, 1534–1546 (2016).
pubmed: 27227735
doi: 10.1002/hep.28659
Lu, J., Chatterjee, M., Schmid, H., Beck, S. & Gawaz, M. CXCL14 as an emerging immune and inflammatory modulator. J. Inflamm. (Lond.) 13, 1 (2016).
doi: 10.1186/s12950-015-0109-9
Cereijo, R. et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 28, 750–763 (2018). This study describes the release of CXCL14 by BAT into the circulation in response to cold exposure, resulting in increased WAT browning and BAT activation via M2 macrophage recruitment.
pubmed: 30122557
doi: 10.1016/j.cmet.2018.07.015
Pedersen, B. K. & Febbraio, M. A. Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, (814–816 (2007).
Schmidt-Arras, D. & Rose-John, S. IL-6 pathway in the liver: from physiopathology to therapy. J. Hepatol. 64, 1403–1415 (2016).
pubmed: 26867490
doi: 10.1016/j.jhep.2016.02.004
Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).
pubmed: 9398739
Zhang, W. et al. Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity. J. Biol. Chem. 289, 32178–32185 (2014).
pubmed: 25253697
pmcid: 4231693
doi: 10.1074/jbc.M114.601096
Matsubara, T. et al. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metab. 15, 38–50 (2012).
pubmed: 22225875
doi: 10.1016/j.cmet.2011.12.002
Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).
pubmed: 19056984
pmcid: 2643026
doi: 10.1126/science.1160794
Wunderlich, F. T. et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237–249 (2010).
pubmed: 20816090
doi: 10.1016/j.cmet.2010.06.011
Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).
pubmed: 24681566
pmcid: 4161471
doi: 10.1038/ni.2865
Braune, J. et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198, 2927–2934 (2017).
pubmed: 28193830
doi: 10.4049/jimmunol.1600476
Theurich, S. et al. IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab. 26, 171–184 (2017).
pubmed: 28683285
doi: 10.1016/j.cmet.2017.05.018
Xu, E. et al. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat. Commun. 8, 14803 (2017).
pubmed: 28466852
pmcid: 5418621
doi: 10.1038/ncomms14803
Schwartz, D. R. & Lazar, M. A. Human resistin: found in translation from mouse to man. Trends Endocrinol. Metab. 22, 259–265 (2011).
pubmed: 21497511
pmcid: 3130099
Tan, Y. et al. Antiresistin RNA oligonucleotide ameliorates diet-induced nonalcoholic fatty liver disease in mice through attenuating proinflammatory cytokines. Biomed. Res. Int. 2015, 414860 (2015).
pubmed: 25922835
pmcid: 4397480
Benomar, Y. et al. Central resistin/TLR4 impairs adiponectin signaling, contributing to insulin and FGF21 resistance. Diabetes 65, 913–926 (2016).
pubmed: 26740596
doi: 10.2337/db15-1029
Savage, D. B. et al. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 50, 2199–2202 (2001).
pubmed: 11574398
doi: 10.2337/diabetes.50.10.2199
Qatanani, M., Szwergold, N. R., Greaves, D. R., Ahima, R. S. & Lazar, M. A. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J. Clin. Invest. 119, 531–539 (2009).
pubmed: 19188682
pmcid: 2648673
doi: 10.1172/JCI37273
Corre, J., Hebraud, B. & Bourin, P. Concise review: growth differentiation factor 15 in pathology: a clinical role? Stem Cells Transl Med. 2, 946–952 (2013).
pubmed: 24191265
pmcid: 3841089
doi: 10.5966/sctm.2013-0055
Ding, Q. et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology 150, 1688–1696 (2009).
pubmed: 19074584
doi: 10.1210/en.2008-0952
Lee, S. E. et al. Growth differentiation factor 15 mediates systemic glucose regulatory action of T-helper type 2 cytokines. Diabetes 66, 2774–2788 (2017).
pubmed: 28874416
doi: 10.2337/db17-0333
Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).
pubmed: 28953886
doi: 10.1038/nature24042
Emmerson, P. J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23, 1215–1219 (2017).
pubmed: 28846098
doi: 10.1038/nm.4393
Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017).
pubmed: 28846097
doi: 10.1038/nm.4392
Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl Med. 9, eaan8732 (2017). This study showed that pharmacological administration of a GDF15 analogue reduces body weight and improves metabolism in obese rodents and monkeys.
pubmed: 29046435
doi: 10.1126/scitranslmed.aan8732
Fukuhara, A. et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426–430 (2005).
pubmed: 15604363
doi: 10.1126/science.1097243
Carbone, F. et al. Regulation and function of extracellular nicotinamide phosphoribosyltransferase/visfatin. Compr. Physiol. 7, 603–621 (2017).
pubmed: 28333382
doi: 10.1002/cphy.c160029
Stromsdorfer, K. L. et al. NAMPT-mediated NAD
pubmed: 27498863
pmcid: 5094180
doi: 10.1016/j.celrep.2016.07.027
Xia, M. et al. Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin. Am. J. Pathol. 184, 1617–1628 (2014).
pubmed: 24631027
pmcid: 4005976
doi: 10.1016/j.ajpath.2014.01.032
Kieswich, J. et al. Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment. Diabetologia 59, 2477–2486 (2016).
pubmed: 27541013
pmcid: 5506101
doi: 10.1007/s00125-016-4076-3
Wesener, D. A. et al. Recognition of microbial glycans by human intelectin-1. Nat. Struct. Mol. Biol. 22, 603–610 (2015).
pubmed: 26148048
pmcid: 4526365
doi: 10.1038/nsmb.3053
Yang, R. Z. et al. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am. J. Physiol. Endocrinol. Metab. 290, E1253–E1261 (2006).
pubmed: 16531507
doi: 10.1152/ajpendo.00572.2004
Watanabe, T., Watanabe-Kominato, K., Takahashi, Y., Kojima, M. & Watanabe, R. Adipose tissue-derived omentin-1 function and regulation. Compr. Physiol. 7, 765–781 (2017).
pubmed: 28640441
doi: 10.1002/cphy.c160043
Tan, B. K. et al. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 57, 801–808 (2008).
pubmed: 18174521
doi: 10.2337/db07-0990
Bluher, M. Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine 41, 176–182 (2012).
pubmed: 22139797
doi: 10.1007/s12020-011-9572-0
Kloting, N. et al. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem. Biophys. Res. Commun. 339, 430–436 (2006).
pubmed: 16298335
doi: 10.1016/j.bbrc.2005.11.039
Fain, J. N., Buehrer, B., Bahouth, S. W., Tichansky, D. S. & Madan, A. K. Comparison of messenger RNA distribution for 60 proteins in fat cells versus the nonfat cells of human omental adipose tissue. Metabolism 57, 1005–1015 (2008).
pubmed: 18555844
doi: 10.1016/j.metabol.2008.02.019
Zieger, K. et al. Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo. Cell. Mol. Life Sci. 75, 727–742 (2018).
pubmed: 28932870
doi: 10.1007/s00018-017-2658-y
Chou, S. H. et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl Acad. Sci. USA 108, 6585–6590 (2011).
pubmed: 21464293
doi: 10.1073/pnas.1015674108
pmcid: 3080974
Petersen, K. F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).
pubmed: 12021250
pmcid: 150981
doi: 10.1172/JCI0215001
Perry, R. J. et al. Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis. J. Clin. Invest. 127, 657–669 (2017).
pubmed: 28112679
pmcid: 5272181
doi: 10.1172/JCI88477
Oberlin, D. & Buettner, C. How does leptin restore euglycemia in insulin-deficient diabetes? J. Clin. Invest. 127, 450–453 (2017).
pubmed: 28112680
pmcid: 5272168
doi: 10.1172/JCI91880
Cui, H., Lopez, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat. Rev. Endocrinol. 13, 338–351 (2017).
pubmed: 28232667
doi: 10.1038/nrendo.2016.222
pmcid: 8904083
Levin, B. E. & Lutz, T. A. Amylin and leptin: co-regulators of energy homeostasis and neuronal development. Trends Endocrinol. Metab. 28, 153–164 (2017).
pubmed: 27938937
doi: 10.1016/j.tem.2016.11.004
Li, Z., Kelly, L., Heiman, M., Greengard, P. & Friedman, J. M. Hypothalamic amylin acts in concert with leptin to regulate food intake. Cell Metab. 22, 1059–1067 (2015).
pubmed: 26655697
doi: 10.1016/j.cmet.2015.10.012
Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).
pubmed: 18458326
doi: 10.1073/pnas.0706473105
pmcid: 2438237
Lee, J. et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat. Med. 22, 1023–1032 (2016). In this study the plant-derived molecule withaferin A was identified as a leptin sensitizer that reduces body weight and improves glucose homeostasis of diet-induced obese mice.
pubmed: 27479085
pmcid: 5892415
doi: 10.1038/nm.4145
Saxena, N. K. & Anania, F. A. Adipocytokines and hepatic fibrosis. Trends Endocrinol. Metab. 26, 153–161 (2015).
pubmed: 25656826
pmcid: 4718075
doi: 10.1016/j.tem.2015.01.002
Kubota, T. et al. Pioglitazone ameliorates smooth muscle cell proliferation in cuff-induced neointimal formation by both adiponectin-dependent and -independent pathways. Sci. Rep. 6, 34707 (2016).
pubmed: 27703271
pmcid: 5050439
doi: 10.1038/srep34707
Zhou, M. et al. Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin. J. Hepatol. 53, 1108–1116 (2010).
pubmed: 20828853
doi: 10.1016/j.jhep.2010.05.034
Okada-Iwabu, M. et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503, 493–499 (2013).
pubmed: 24172895
doi: 10.1038/nature12656
Yamashita, T. et al. An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis. Sci. Rep. 8, 11843 (2018).
pubmed: 30087356
pmcid: 6081386
doi: 10.1038/s41598-018-29901-w
Menzaghi, C. & Trischitta, V. The adiponectin paradox for all-cause and cardiovascular mortality. Diabetes 67, 12–22 (2018).
pubmed: 29263167
doi: 10.2337/dbi17-0016
Aleksandrova, K., Mozaffarian, D. & Pischon, T. Addressing the perfect storm: biomarkers in obesity and pathophysiology of cardiometabolic risk. Clin. Chem. 64, 142–153 (2018).
pubmed: 29138271
doi: 10.1373/clinchem.2017.275172
Zoi, I. et al. RANKL signaling and ErbB receptors in breast carcinogenesis. Trends Mol. Med. 22, 839–850 (2016).
pubmed: 27567286
doi: 10.1016/j.molmed.2016.07.009
Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).
pubmed: 15902306
pmcid: 1088017
doi: 10.1172/JCI23606
Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019).
pubmed: 30554783
doi: 10.1016/S0140-6736(18)31785-9
Kataoka, Y. et al. Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. J. Am. Coll. Cardiol. 63, 2722–2733 (2014).
pubmed: 24768874
doi: 10.1016/j.jacc.2014.03.032
Matsuo, K. et al. Omentin functions to attenuate cardiac hypertrophic response. J. Mol. Cell Cardiol. 79, 195–202 (2015).
pubmed: 25479337
doi: 10.1016/j.yjmcc.2014.11.019
Hiramatsu-Ito, M. et al. Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice. Cardiovasc. Res. 110, 107–117 (2016).
pubmed: 26714927
doi: 10.1093/cvr/cvv282
Yuan, L. et al. Vaspin protects rats against myocardial ischemia/reperfusion injury (MIRI) through the TLR4/NF-kappaB signaling pathway. Eur. J. Pharmacol. 835, 132–139 (2018).
pubmed: 30063916
doi: 10.1016/j.ejphar.2018.07.052
Sakamoto, Y. et al. Visceral adipose tissue-derived serine protease inhibitor prevents the development of monocrotaline-induced pulmonary arterial hypertension in rats. Pflugers Arch. 469, 1425–1432 (2017).
pubmed: 28776262
doi: 10.1007/s00424-017-2043-6
O’Neill, S. M. et al. Targeting adipose tissue via systemic gene therapy. Gene Ther. 21, 653–661 (2014).
pubmed: 24830434
pmcid: 4342115
doi: 10.1038/gt.2014.38
Aouadi, M. et al. Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc. Natl Acad. Sci. USA 110, 8278–8283 (2013). This study describes a method to selectively target small interfering RNAs to macrophages in epididymal WAT but not subcutaneous WAT or other organs.
pubmed: 23630254
doi: 10.1073/pnas.1300492110
pmcid: 3657808
Chang, H. R., Kim, H. J., Xu, X. & Ferrante, A. W. Jr. Macrophage and adipocyte IGF1 maintain adipose tissue homeostasis during metabolic stresses. Obesity (Silver Spring) 24, 172–183 (2016).
doi: 10.1002/oby.21354
Almuraikhy, S. et al. Interleukin-6 induces impairment in human subcutaneous adipogenesis in obesity-associated insulin resistance. Diabetologia 59, 2406–2416 (2016).
pubmed: 27342408
pmcid: 5506102
doi: 10.1007/s00125-016-4031-3
Weiner, J. et al. Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation. Mol. Metab. 6, 482–493 (2017).
pubmed: 28580279
pmcid: 5444018
doi: 10.1016/j.molmet.2017.03.004