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Metabolic interplay between white, beige, brown adipocytes and the liver

  • Ludger Scheja
    Affiliations
    Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
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  • Joerg Heeren
    Correspondence
    Corresponding author. Address: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Tel.: +49 40 7410 54745.
    Affiliations
    Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
    Search for articles by this author
Published:January 29, 2016DOI:https://doi.org/10.1016/j.jhep.2016.01.025

      Summary

      In mammalian evolution, three types of adipocytes have developed, white, brown and beige adipocytes. White adipocytes are the major constituents of white adipose tissue (WAT), the predominant store for energy-dense triglycerides in the body that are released as fatty acids during catabolic conditions. The less abundant brown adipocytes, the defining parenchymal cells of brown adipose tissue (BAT), internalize triglycerides that are stored intracellularly in multilocular lipid droplets. Beige adipocytes (also known as brite or inducible brown adipocytes) are functionally very similar to brown adipocytes and emerge in specific WAT depots in response to various stimuli including sustained cold exposure. The activation of brown and beige adipocytes (together referred to as thermogenic adipocytes) causes both the hydrolysis of stored triglycerides as well as the uptake of lipids and glucose from the circulation. Together, these fuels are combusted for heat production to maintain body temperature in mammals including adult humans. Given that heating by brown and beige adipocytes is a very-well controlled and energy-demanding process which entails pronounced shifts in energy fluxes, it is not surprising that an intensive interplay exists between the various adipocyte types and parenchymal liver cells, and that this influences systemic metabolic fluxes and endocrine networks. In this review we will emphasize the role of hepatic factors that regulate the metabolic activity of white and thermogenic adipocytes. In addition, we will discuss the relevance of lipids and hormones that are secreted by white, brown and beige adipocytes regulating liver metabolism in order to maintain systemic energy metabolism in health and disease.

      Keywords

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      References

        • Rosen E.D.
        • Spiegelman B.M.
        What we talk about when we talk about fat.
        Cell. 2014; 156: 20-44
        • Tchernof A.
        • Després J.P.
        Pathophysiology of human visceral obesity: an update.
        Physiol Rev. 2013; 93: 359-404
        • Young S.G.
        • Zechner R.
        Biochemistry and pathophysiology of intravascular and intracellular lipolysis.
        Genes Dev. 2013; 27: 459-484
        • Jeppesen J.
        • Kiens B.
        Regulation and limitations to fatty acid oxidation during exercise.
        J Physiol. 2012; 590: 1059-1068
        • Donnelly K.L.
        • Smith C.I.
        • Schwarzenberg S.J.
        • Jessurun J.
        • Boldt M.D.
        • Parks E.J.
        Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
        J Clin Invest. 2005; 115: 1343-1351
        • Barrows B.R.
        • Parks E.J.
        Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states.
        J Clin Endocrinol Metab. 2006; 91: 1446-1452
        • Kersten S.
        Physiological regulation of lipoprotein lipase.
        Biochim Biophys Acta. 2014; 1841: 919-933
        • Broedl U.C.
        • Maugeais C.
        • Millar J.S.
        • Jin W.
        • Moore R.E.
        • Fuki I.V.
        • et al.
        Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins.
        Circ Res. 2004; 94: 1554-1561
        • Fielding B.
        Tracing the fate of dietary fatty acids: metabolic studies of postprandial lipaemia in human subjects.
        Proc Nutr Soc. 2011; 70: 342-350
        • Sadur C.N.
        • Eckel R.H.
        Insulin stimulation of adipose tissue lipoprotein lipase. Use of the euglycemic clamp technique.
        J Clin Invest. 1982; 69: 1119-1125
        • Chirieac D.V.
        • Chirieac L.R.
        • Corsetti J.P.
        • Cianci J.
        • Sparks C.E.
        • Sparks J.D.
        Glucose-stimulated insulin secretion suppresses hepatic triglyceride-rich lipoprotein and apoB production.
        Am J Physiol Endocrinol Metab. 2000; 279: E1003-E1011
        • Kim T.S.
        • Freake H.C.
        High carbohydrate diet and starvation regulate lipogenic mRNA in rats in a tissue-specific manner.
        J Nutr. 1996; 126: 611-617
        • Hellerstein M.K.
        De novo lipogenesis in humans: metabolic and regulatory aspects.
        Eur J Clin Nutr. 1999; 53: S53-S65
        • Postic C.
        • Girard J.
        Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.
        J Clin Invest. 2008; 118: 829-838
        • Herman M.A.
        • Peroni O.D.
        • Villoria J.
        • Schön M.R.
        • Abumrad N.A.
        • Blüher M.
        • et al.
        A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism.
        Nature. 2012; 484: 333-338
        • Himms-Hagen J.
        Does thermoregulatory feeding occur in newborn infants? A novel view of the role of brown adipose tissue thermogenesis in control of food intake.
        Obes Res. 1995; 3: 361-369
        • Cinti S.
        The adipose organ: morphological perspectives of adipose tissues.
        Proc Nutr Soc. 2001; 60: 319-328
        • Lidell M.E.
        • Betz M.J.
        • Dahlqvist Leinhard O.
        • Heglind M.
        • Elander L.
        • Slawik M.
        • et al.
        Evidence for two types of brown adipose tissue in humans.
        Nat Med. 2013; 19: 631-634
        • Bartelt A.
        • Heeren J.
        Adipose tissue browning and metabolic health.
        Nat Rev Endocrinol. 2014; 10: 24-36
        • Virtanen K.A.
        • Lidell M.E.
        • Orava J.
        • Heglind M.
        • Westergren R.
        • Niemi T.
        • et al.
        Functional brown adipose tissue in healthy adults.
        N Engl J Med. 2009; 360: 1518-1525
        • Cypess A.M.
        • Lehman S.
        • Williams G.
        • Tal I.
        • Rodman D.
        • Goldfine A.B.
        • et al.
        Identification and importance of brown adipose tissue in adult humans.
        N Engl J Med. 2009; 360: 1509-1517
        • van Marken Lichtenbelt W.D.
        • Vanhommerig J.W.
        • Smulders N.M.
        • Drossaerts J.M.
        • Kemerink G.J.
        • Bouvy N.D.
        • et al.
        Cold-activated brown adipose tissue in healthy men.
        N Engl J Med. 2009; 360: 1500-1508
        • Cypess A.M.
        • White A.P.
        • Vernochet C.
        • Schulz T.J.
        • Xue R.
        • Sass C.A.
        • et al.
        Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat.
        Nat Med. 2013; 19: 635-639
        • Jespersen N.Z.
        • Larsen T.J.
        • Peijs L.
        • Daugaard S.
        • Homøe P.
        • Loft A.
        • et al.
        A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans.
        Cell Metab. 2013; 17: 798-805
        • Cannon B.
        • Nedergaard J.
        Brown adipose tissue: function and physiological significance.
        Physiol Rev. 2004; 84: 277-359
        • Bartelt A.
        • Bruns O.T.
        • Reimer R.
        • Hohenberg H.
        • Ittrich H.
        • Peldschus K.
        • et al.
        Brown adipose tissue activity controls triglyceride clearance.
        Nat Med. 2011; 17: 200-205
        • Stanford K.I.
        • Middelbeek R.J.
        • Townsend K.L.
        • An D.
        • Nygaard E.B.
        • Hitchcox K.M.
        • et al.
        Brown adipose tissue regulates glucose homeostasis and insulin sensitivity.
        J Clin Invest. 2013; 123: 215-223
        • Heeren J.
        • Münzberg H.
        Novel aspects of brown adipose tissue biology.
        Endocrinol Metab Clin North Am. 2013; 42: 89-107
        • Watanabe M.
        • Houten S.M.
        • Mataki C.
        • Christoffolete M.A.
        • Kim B.W.
        • Sato H.
        • et al.
        Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.
        Nature. 2006; 439: 484-489
        • Broeders E.P.
        • Nascimento E.B.
        • Havekes B.
        • Brans B.
        • Roumans K.H.
        • Tailleux A.
        • et al.
        The bile acid chenodeoxycholic acid increases human brown adipose tissue activity.
        Cell Metab. 2015; 22: 418-426
        • Bordicchia M.
        • Liu D.
        • Amri E.Z.
        • Ailhaud G.
        • Dessì-Fulgheri P.
        • Zhang C.
        • et al.
        Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.
        J Clin Invest. 2012; 122: 1022-1036
        • Gnad T.
        • Scheibler S.
        • von Kügelgen I.
        • Scheele C.
        • Kilić A.
        • Glöde A.
        • et al.
        Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.
        Nature. 2014; 516: 395-399
        • Bartelt A.
        • Heeren J.
        The holy grail of metabolic disease: brown adipose tissue.
        Curr Opin Lipidol. 2012; 23: 190-195
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • Cohen J.C.
        • Cox D.R.
        • Fruchart J.C.
        • et al.
        An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
        Science. 2001; 294: 169-173
        • Hoffer M.J.
        • van Eck M.M.
        • Havekes L.M.
        • Hofker M.H.
        • Frants R.R.
        Structure and expression of the mouse apolipoprotein C2 gene.
        Genomics. 1993; 17: 45-51
        • Breckenridge W.C.
        • Little J.A.
        • Steiner G.
        • Chow A.
        • Poapst M.
        Hypertriglyceridemia associated with deficiency of apolipoprotein C-II.
        N Engl J Med. 1978; 298: 1265-1273
        • Albers K.
        • Schlein C.
        • Wenner K.
        • Lohse P.
        • Bartelt A.
        • Heeren J.
        • et al.
        Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant.
        Atherosclerosis. 2014; 233: 97-103
        • Nowak M.
        • Helleboid-Chapman A.
        • Jakel H.
        • Moitrot E.
        • Rommens C.
        • Pennacchio L.A.
        • et al.
        Glucose regulates the expression of the apolipoprotein A5 gene.
        J Mol Biol. 2008; 380: 789-798
        • Camporez J.P.
        • Kanda S.
        • Petersen M.C.
        • Jornayvaz F.R.
        • Samuel V.T.
        • Bhanot S.
        • et al.
        ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content.
        J Lipid Res. 2015; 56: 526-536
        • Norata G.D.
        • Tsimikas S.
        • Pirillo A.
        • Catapano A.L.
        Apolipoprotein C-III: from pathophysiology to pharmacology.
        Trends Pharmacol Sci. 2015; 36: 675-687
        • Duivenvoorden I.
        • Teusink B.
        • Rensen P.C.
        • Romijn J.A.
        • Havekes L.M.
        • Voshol P.J.
        Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice.
        Diabetes. 2005; 54: 664-671
        • Kim J.K.
        • Fillmore J.J.
        • Chen Y.
        • Yu C.
        • Moore I.K.
        • Pypaert M.
        • et al.
        Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.
        Proc Natl Acad Sci U S A. 2001; 98: 7522-7527
        • Baldi S.
        • Bonnet F.
        • Laville M.
        • Morgantini C.
        • Monti L.
        • Hojlund K.
        • et al.
        Influence of apolipoproteins on the association between lipids and insulin sensitivity: a cross-sectional analysis of the RISC Study.
        Diabetes Care. 2013; 36: 4125-4131
        • Fugier C.
        • Tousaint J.J.
        • Prieur X.
        • Plateroti M.
        • Samarut J.
        • Delerive P.
        The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone.
        J Biol Chem. 2006; 281: 11553-11559
        • Shimamura M.
        • Matsuda M.
        • Ando Y.
        • Koishi R.
        • Yasumo H.
        • Furukawa H.
        • et al.
        Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor.
        Biochem Biophys Res Commun. 2004; 322: 1080-1085
        • Lu B.
        • Moser A.
        • Shigenaga J.K.
        • Grunfeld C.
        • Feingold K.R.
        The acute phase response stimulates the expression of angiopoietin like protein 4.
        Biochem Biophys Res Commun. 2010; 391: 1737-1741
        • Arca M.
        • Minicocci I.
        • Maranghi M.
        The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism.
        Curr Opin Lipidol. 2013; 24: 313-320
        • Robciuc M.R.
        • Maranghi M.
        • Lahikainen A.
        • Rader D.
        • Bensadoun A.
        • Öörni K.
        • et al.
        Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids.
        Arterioscler Thromb Vasc Biol. 2013; 33: 1706-1713
        • Wang Y.
        • Quagliarini F.
        • Gusarova V.
        • Gromada J.
        • Valenzuela D.M.
        • Cohen J.C.
        • et al.
        Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.
        Proc Natl Acad Sci U S A. 2013; 110: 16109-16114
        • Quagliarini F.
        • Wang Y.
        • Kozlitina J.
        • Grishin N.V.
        • Hyde R.
        • Boerwinkle E.
        • et al.
        Atypical angiopoietin-like protein that regulates ANGPTL3.
        Proc Natl Acad Sci U S A. 2012; 109: 19751-19756
        • Wang Y.
        • McNutt M.C.
        • Banfi S.
        • Levin M.G.
        • Holland W.L.
        • Gusarova V.
        • et al.
        Hepatic ANGPTL3 regulates adipose tissue energy homeostasis.
        Proc Natl Acad Sci U S A. 2015; 112: 11630-11635
        • Stefan N.
        • Häring H.U.
        The role of hepatokines in metabolism.
        Nat Rev Endocrinol. 2013; 9: 144-152
        • Kharitonenkov A.
        • DiMarchi R.
        FGF21 revolutions: recent advances illuminating FGF21 biology and medicinal properties.
        Trends Endocrinol Metab. 2015; (pii: S1043-2760(15)00184-8. Epub ahead of print)
        • Badman M.K.
        • Pissios P.
        • Kennedy A.R.
        • Koukos G.
        • Flier J.S.
        • Maratos-Flier E.
        Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
        Cell Metab. 2007; 5: 426-437
        • Inagaki T.
        • Dutchak P.
        • Zhao G.
        • Ding X.
        • Gautron L.
        • Parameswara V.
        • et al.
        Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.
        Cell Metab. 2007; 5: 415-425
        • Markan K.R.
        • Naber M.C.
        • Ameka M.K.
        • Anderegg M.D.
        • Mangelsdorf D.J.
        • Kliewer S.A.
        • et al.
        Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding.
        Diabetes. 2014; 63: 4057-4063
        • Hotta Y.
        • Nakamura H.
        • Konishi M.
        • Murata Y.
        • Takagi H.
        • Matsumura S.
        • et al.
        Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver.
        Endocrinology. 2009; 150: 4625-4633
        • Fisher F.M.
        • Kleiner S.
        • Douris N.
        • Fox E.C.
        • Mepani R.J.
        • Verdeguer F.
        • et al.
        FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis.
        Genes Dev. 2012; 26: 271-281
        • Owen B.M.
        • Ding X.
        • Morgan D.A.
        • Coate K.C.
        • Bookout A.L.
        • Rahmouni K.
        • et al.
        FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss.
        Cell Metab. 2014; 20: 670-677
        • Rojas J.M.
        • Matsen M.E.
        • Mundinger T.O.
        • Morton G.J.
        • Stefanovski D.
        • Bergman R.N.
        • et al.
        Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response.
        Mol Metab. 2015; 4: 561-568
        • Douris N.
        • Stevanovic D.M.
        • Fisher F.M.
        • Cisu T.I.
        • Chee M.J.
        • Nguyen N.L.
        • et al.
        Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice.
        Endocrinology. 2015; 156: 2470-2481
        • Zhang X.
        • Yeung D.C.
        • Karpisek M.
        • Stejskal D.
        • Zhou Z.G.
        • Liu F.
        • et al.
        Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
        Diabetes. 2008; 57: 1246-1253
        • Yang C.
        • Lu W.
        • Lin T.
        • You P.
        • Ye M.
        • Huang Y.
        • et al.
        Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.
        BMC Gastroenterol. 2013; 13: 67
        • Dushay J.R.
        • Toschi E.
        • Mitten E.K.
        • Fisher F.M.
        • Herman M.A.
        • Maratos-Flier E.
        Fructose ingestion acutely stimulates circulating FGF21 levels in humans.
        Mol Metab. 2014; 4: 51-57
        • Berti L.
        • Irmler M.
        • Zdichavsky M.
        • Meile T.
        • Böhm A.
        • Stefan N.
        • et al.
        Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes.
        Mol Metab. 2015; 4: 519-527
        • Stefan N.
        • Fritsche A.
        • Weikert C.
        • Boeing H.
        • Joost H.G.
        • Häring H.U.
        • et al.
        Plasma fetuin-A levels and the risk of type 2 diabetes.
        Diabetes. 2008; 57: 2762-2767
        • Pal D.
        • Dasgupta S.
        • Kundu R.
        • Maitra S.
        • Das G.
        • Mukhopadhyay S.
        • et al.
        Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.
        Nat Med. 2012; 18: 1279-1285
        • Hennige A.M.
        • Staiger H.
        • Wicke C.
        • Machicao F.
        • Fritsche A.
        • Häring H.U.
        • et al.
        Fetuin-A induces cytokine expression and suppresses adiponectin production.
        PLoS One. 2008; 3e1765
        • Chatterjee P.
        • Seal S.
        • Mukherjee S.
        • Kundu R.
        • Mukherjee S.
        • Ray S.
        • et al.
        Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages.
        J Biol Chem. 2013; 288: 28324-28330
        • Choi C.S.
        • Ghoshal P.
        • Srinivasan M.
        • Kim S.
        • Cline G.
        • Patel M.S.
        Liver-specific pyruvate dehydrogenase complex deficiency upregulates lipogenesis in adipose tissue and improves peripheral insulin sensitivity.
        Lipids. 2010; 45: 987-995
        • Knowles C.
        • Liu Z.M.
        • Yang J.
        Compensatory increase in lipogenic gene expression in adipose tissue of transgenic mice expressing constitutively active AMP-activated protein kinase-alpha1 in liver.
        Biochem Biophys Res Commun. 2011; 412: 249-252
        • Kuriyama H.
        • Liang G.
        • Engelking L.J.
        • Horton J.D.
        • Goldstein J.L.
        • Brown M.S.
        Compensatory increase in fatty acid synthesis in adipose tissue of mice with conditional deficiency of SCAP in liver.
        Cell Metab. 2005; 1: 41-51
        • Burhans M.S.
        • Flowers M.T.
        • Harrington K.R.
        • Bond L.M.
        • Guo C.A.
        • Anderson R.M.
        • et al.
        Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation.
        J Lipid Res. 2015; 56: 304-318
        • Taggart A.K.
        • Kero J.
        • Gan X.
        • Cai T.Q.
        • Cheng K.
        • Ippolito M.
        • et al.
        (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G.
        J Biol Chem. 2005; 22: 26649-26652
        • Plaisance E.P.
        • Lukasova M.
        • Offermanns S.
        • Zhang Y.
        • Cao G.
        • Judd R.L.
        Niacin stimulates adiponectin secretion through the GPR109A receptor.
        Am J Physiol Endocrinol Metab. 2009; 296: E549-E558
        • Digby J.E.
        • McNeill E.
        • Dyar O.J.
        • Lam V.
        • Greaves D.R.
        • Choudhury R.P.
        Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin.
        Atherosclerosis. 2010; 209: 89-95
        • Kuipers F.
        • Bloks V.W.
        • Groen A.K.
        Beyond intestinal soap–bile acids in metabolic control.
        Nat Rev Endocrinol. 2014; 10: 488-498
        • Abdelkarim M.
        • Caron S.
        • Duhem C.
        • Prawitt J.
        • Dumont J.
        • Lucas A.
        • et al.
        The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways.
        J Biol Chem. 2010; 285: 36759-36767
        • Shihabudeen M.S.
        • Roy D.
        • James J.
        • Thirumurugan K.
        Chenodeoxycholic acid, an endogenous FXR ligand alters adipokines and reverses insulin resistance.
        Mol Cell Endocrinol. 2015; 414: 19-28
        • Mottillo E.P.
        • Bloch A.E.
        • Leff T.
        • Granneman J.G.
        Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) α and δ in brown adipocytes to match fatty acid oxidation with supply.
        J Biol Chem. 2012; 287: 25038-25048
        • Dempersmier J.
        • Sambeat A.
        • Gulyaeva O.
        • Paul S.M.
        • Hudak C.S.
        • Raposo H.F.
        • et al.
        Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat.
        Mol Cell. 2015; 57: 235-246
        • Chang J.S.
        • Fernand V.
        • Zhang Y.
        • Shin J.
        • Jun H.J.
        • Joshi Y.
        • et al.
        NT-PGC-1α protein is sufficient to link β3-adrenergic receptor activation to transcriptional and physiological components of adaptive thermogenesis.
        J Biol Chem. 2012; 287: 9100-9111
        • Fang S.
        • Suh J.M.
        • Reilly S.M.
        • Yu E.
        • Osborn O.
        • Lackey D.
        • et al.
        Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.
        Nat Med. 2015; 21: 159-165
        • Ryan K.K.
        • Tremaroli V.
        • Clemmensen C.
        • Kovatcheva-Datchary P.
        • Myronovych A.
        • Karns R.
        • et al.
        FXR is a molecular target for the effects of vertical sleeve gastrectomy.
        Nature. 2014; 509: 183-188
        • Byrne C.D.
        • Targher G.
        NAFLD: a multisystem disease.
        J Hepatol. 2015; 62: S47-S64
        • Patni N.
        • Garg A.
        Congenital generalized lipodystrophies–new insights into metabolic dysfunction.
        Nat Rev Endocrinol. 2015; 11: 522-534
        • Fasshauer M.
        • Blüher M.
        Adipokines in health and disease.
        Trends Pharmacol Sci. 2015; 36: 461-470
        • Arita Y.
        • Kihara S.
        • Ouchi N.
        • Takahashi M.
        • Maeda K.
        • Miyagawa J.
        • et al.
        Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
        Biochem Biophys Res Commun. 1999; 257: 79-83
        • Xu A.
        • Wang Y.
        • Keshaw H.
        • Xu L.Y.
        • Lam K.S.
        • Cooper G.J.
        The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.
        J Clin Invest. 2003; 112: 91-100
        • Berg A.H.
        • Combs T.P.
        • Du X.
        • Brownlee M.
        • Scherer P.E.
        The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
        Nat Med. 2001; 7: 947-953
        • Awazawa M.
        • Ueki K.
        • Inabe K.
        • Yamauchi T.
        • Kubota N.
        • Kaneko K.
        • et al.
        Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway.
        Cell Metab. 2011; 13: 401-412
        • 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. 2011; 286: 13460-13469
        • Okada-Iwabu M.
        • Yamauchi T.
        • Iwabu M.
        • Honma T.
        • Hamagami K.
        • Matsuda K.
        • et al.
        A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.
        Nature. 2013; 503: 493-499
        • Peng Y.
        • Rideout D.
        • Rakita S.
        • Sajan M.
        • Farese R.
        • You M.
        • et al.
        Downregulation of adiponectin/AdipoR2 is associated with steatohepatitis in obese mice.
        J Gastrointest Surg. 2009; 13: 2043-2049
        • Handa P.
        • Maliken B.D.
        • Nelson J.E.
        • Morgan-Stevenson V.
        • Messner D.J.
        • Dhillon B.K.
        • et al.
        Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis.
        Hepatology. 2014; 60: 133-145
        • Hui J.M.
        • Hodge A.
        • Farrell G.C.
        • Kench J.G.
        • Kriketos A.
        • George J.
        Beyond insulin resistance in NASH: TNF-alpha or adiponectin?.
        Hepatology. 2004; 40: 46-54
        • Bugianesi E.
        • Pagotto U.
        • Manini R.
        • Vanni E.
        • Gastaldelli A.
        • de Iasio R.
        • et al.
        Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity.
        J Clin Endocrinol Metab. 2005; 90: 3498-3504
        • Turer A.T.
        • Khera A.
        • Ayers C.R.
        • Turer C.B.
        • Grundy S.M.
        • Vega G.L.
        • et al.
        Adipose tissue mass and location affect circulating adiponectin levels.
        Diabetologia. 2011; 54: 2515-2524
        • Yamauchi T.
        • Nio Y.
        • Maki T.
        • Kobayashi M.
        • Takazawa T.
        • Iwabu M.
        • et al.
        Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.
        Nat Med. 2007; 13: 332-339
        • Asilmaz E.
        • Cohen P.
        • Miyazaki M.
        • Dobrzyn P.
        • Ueki K.
        • Fayzikhodjaeva G.
        • et al.
        Site and mechanism of leptin action in a rodent form of congenital lipodystrophy.
        J Clin Invest. 2004; 113: 414-424
        • Miyamoto L.
        • Ebihara K.
        • Kusakabe T.
        • Aotani D.
        • Yamamoto-Kataoka S.
        • Sakai T.
        • et al.
        Leptin activates hepatic 5’-AMP-activated protein kinase through sympathetic nervous system and á1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin.
        J Biol Chem. 2012; 287: 40441-40447
        • Safar Zadeh E.
        • Lungu A.O.
        • Cochran E.K.
        • Brown R.J.
        • Ghany M.G.
        • Heller T.
        • et al.
        The liver diseases of lipodystrophy: the long-term effect of leptin treatment.
        J Hepatol. 2013; 59: 131-137
        • Imajo K.
        • Fujita K.
        • Yoneda M.
        • Nozaki Y.
        • Ogawa Y.
        • Shinohara Y.
        • et al.
        Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling.
        Cell Metab. 2012; 16: 44-54
        • Chatterjee S.
        • Ganini D.
        • Tokar E.J.
        • Kumar A.
        • Das S.
        • Corbett J.
        • et al.
        Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis.
        J Hepatol. 2013; 58: 778-784
        • Leclercq I.A.
        • Farrell G.C.
        • Schriemer R.
        • Robertson G.R.
        Leptin is essential for the hepatic fibrogenic response to chronic liver injury.
        J Hepatol. 2002; 37: 206-213
        • Yu X.
        • Park B.H.
        • Wang M.Y.
        • Wang Z.V.
        • Unger R.H.
        Making insulin-deficient type 1 diabetic rodents thrive without insulin.
        Proc Natl Acad Sci U S A. 2008; 105: 14070-14075
        • Cummings B.P.
        • Bettaieb A.
        • Graham J.L.
        • Stanhope K.L.
        • Dill R.
        • Morton G.J.
        • et al.
        Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats.
        Proc Natl Acad Sci U S A. 2011; 108: 14670-14675
        • Chitturi S.
        • Farrell G.
        • Frost L.
        • Kriketos A.
        • Lin R.
        • Fung C.
        • et al.
        Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?.
        Hepatology. 2002; 36: 403-409
        • Musso G.
        • Gambino R.
        • Durazzo M.
        • Biroli G.
        • Carello M.
        • Fagà E.
        • et al.
        Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease.
        Hepatology. 2005; 42: 1175-1183
        • Polyzos S.A.
        • Aronis K.N.
        • Kountouras J.
        • Raptis D.D.
        • Vasiloglou M.F.
        • Mantzoros C.S.
        Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
        Diabetologia. 2016; 59: 30-43
        • Fontana L.
        • Eagon J.C.
        • Trujillo M.E.
        • Scherer P.E.
        • Klein S.
        Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.
        Diabetes. 2007; 56: 1010-1013
        • Min H.K.
        • Mirshahi F.
        • Verdianelli A.
        • Pacana T.
        • Patel V.
        • Park C.G.
        • et al.
        Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease.
        Am J Physiol Gastrointest Liver Physiol. 2015; 308: G794-G803
        • Rytka J.M.
        • Wueest S.
        • Schoenle E.J.
        • Konrad D.
        The portal theory supported by venous drainage-selective fat transplantation.
        Diabetes. 2011; 60: 56-63
        • Hocking S.L.
        • Stewart R.L.
        • Brandon A.E.
        • Suryana E.
        • Stuart E.
        • Baldwin E.M.
        • et al.
        Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice.
        Diabetologia. 2015; 58: 1587-1600
        • Mauer J.
        • Chaurasia B.
        • Goldau J.
        • Vogt M.C.
        • Ruud J.
        • Nguyen K.D.
        • et al.
        Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin.
        Nat Immunol. 2014; 15: 423-430
        • Reilly S.M.
        • Ahmadian M.
        • Zamarron B.F.
        • Chang L.
        • Uhm M.
        • Poirier B.
        • et al.
        A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.
        Nat Commun. 2015; 6: 6047
        • Nov O.
        • Shapiro H.
        • Ovadia H.
        • Tarnovscki T.
        • Dvir I.
        • Shemesh E.
        • et al.
        Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability.
        PLoS One. 2013; 8e53626
        • Fabbrini E.
        • Cella M.
        • McCartney S.A.
        • Fuchs A.
        • Abumrad N.A.
        • Pietka T.A.
        • et al.
        Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals.
        Gastroenterology. 2013; 145: 366-374
        • Pardo V.
        • González-Rodríguez Á.
        • Guijas C.
        • Balsinde J.
        • Valverde Á.M.
        Opposite cross-talk by oleate and palmitate on insulin signaling in hepatocytes through macrophage activation.
        J Biol Chem. 2015; 290: 11663-11677
        • Miura K.
        • Yang L.
        • van Rooijen N.
        • Brenner D.A.
        • Ohnishi H.
        • Seki E.
        Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.
        Hepatology. 2013; 57: 577-589
        • Leroux A.
        • Ferrere G.
        • Godie V.
        • Cailleux F.
        • Renoud M.L.
        • Gaudin F.
        • et al.
        Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis.
        J Hepatol. 2012; 57: 141-149
        • Tencerova M.
        • Aouadi M.
        • Vangala P.
        • Nicoloro S.M.
        • Yawe J.C.
        • Cohen J.L.
        • et al.
        Activated Kupffer cells inhibit insulin sensitivity in obese mice.
        FASEB J. 2015; 29: 2959-2969
        • Dixon L.J.
        • Flask C.A.
        • Papouchado B.G.
        • Feldstein A.E.
        • Nagy L.E.
        Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis.
        PLoS One. 2013; 8e56100
        • Raptis D.A.
        • Limani P.
        • Jang J.H.
        • Ungethüm U.
        • Tschuor C.
        • Graf R.
        • et al.
        GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids.
        J Hepatol. 2014; 60: 625-632
        • Jaworski K.
        • Ahmadian M.
        • Duncan R.E.
        • Sarkadi-Nagy E.
        • Varady K.A.
        • Hellerstein M.K.
        • et al.
        AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency.
        Nat Med. 2009; 15: 159-168
        • Cao H.
        • Gerhold K.
        • Mayers J.R.
        • Wiest M.M.
        • Watkins S.M.
        • Hotamisligil G.S.
        Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.
        Cell. 2008; 134: 933-944
        • Koeberle A.
        • Shindou H.
        • Harayama T.
        • Shimizu T.
        Palmitoleate is a mitogen, formed upon stimulation with growth factors, and converted to palmitoleoyl-phosphatidylinositol.
        J Biol Chem. 2012; 287: 27244-27254
        • Tripathy S.
        • Jump D.B.
        Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice.
        J Lipid Res. 2013; 54: 71-84
        • Talbot N.A.
        • Wheeler-Jones C.P.
        • Cleasby M.E.
        Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance.
        Mol Cell Endocrinol. 2014; 393: 129-142
        • 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. 2011; 10: 120
        • Guo X.
        • Li H.
        • Xu H.
        • Halim V.
        • Zhang W.
        • Wang H.
        • et al.
        Palmitoleate induces hepatic steatosis but suppresses liver inflammatory response in mice.
        PLoS One. 2012; 7e39286
        • Eissing L.
        • Scherer T.
        • Tödter K.
        • Knippschild U.
        • Greve J.W.
        • Buurman W.A.
        • et al.
        De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health.
        Nat Commun. 2013; 4: 1528
        • Bernstein A.M.
        • Roizen M.F.
        • Martinez L.
        Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double-blinded, randomized, placebo controlled study.
        J Clin Lipidol. 2014; 8: 612-617
        • Yore M.M.
        • Syed I.
        • Moraes-Vieira P.M.
        • Zhang T.
        • Herman M.A.
        • Homan E.A.
        • et al.
        Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.
        Cell. 2014; 159: 318-332
        • Berbée J.F.
        • Boon M.R.
        • Khedoe P.P.
        • Bartelt A.
        • Schlein C.
        • Worthmann A.
        • et al.
        Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development.
        Nat Commun. 2015; 6: 6356
        • Dong M.
        • Yang X.
        • Lim S.
        • Cao Z.
        • Honek J.
        • Lu H.
        • et al.
        Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.
        Cell Metab. 2013; 18: 118-129
        • Liu X.
        • Zheng Z.
        • Zhu X.
        • Meng M.
        • Li L.
        • Shen Y.
        • et al.
        Brown adipose tissue transplantation improves whole-body energy metabolism.
        Cell Res. 2013; 23: 851-854
        • Liu X.
        • Wang S.
        • You Y.
        • Meng M.
        • Zheng Z.
        • Dong M.
        • et al.
        Brown adipose tissue transplantation reverses obesity in Ob/Ob mice.
        Endocrinology. 2015; 156: 2461-2469
        • van den Beukel J.C.
        • Boon M.R.
        • Steenbergen J.
        • Rensen P.C.
        • Meijer O.C.
        • Themmen A.P.
        • et al.
        Cold exposure partially corrects disturbances in lipid metabolism in a male mouse model of glucocorticoid excess.
        Endocrinology. 2015; 156: 4115-4128
        • Yilmaz Y.
        • Ones T.
        • Purnak T.
        • Ozguven S.
        • Kurt R.
        • Atug O.
        • et al.
        Association between the presence of brown adipose tissue and non-alcoholic fatty liver disease in adult humans.
        Aliment Pharmacol Ther. 2011; 34: 318-323
        • Ozguven S.
        • Ones T.
        • Yilmaz Y.
        • Turoglu H.T.
        • Imeryuz N.
        The role of active brown adipose tissue in human metabolism.
        Eur J Nucl Med Mol Imaging. 2016; 43: 355-361
        • Ouellet V.
        • Labbé S.M.
        • Blondin D.P.
        • Phoenix S.
        • Guérin B.
        • Haman F.
        • et al.
        Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.
        J Clin Invest. 2012; 122: 545-552
        • Blondin D.P.
        • Labbé S.M.
        • Noll C.
        • Kunach M.
        • Phoenix S.
        • Guérin B.
        • et al.
        Selective impairment of glucose but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes.
        Diabetes. 2015; 64: 2388-2397
        • Puerta M.
        • Abelenda M.
        • Rocha M.
        • Trayhurn P.
        Effect of acute cold exposure on the expression of the adiponectin, resistin and leptin genes in rat white and brown adipose tissues.
        Horm Metab Res. 2002; 34: 629-634
        • 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. 2015; 308: E1043-E1055
        • Wang G.X.
        • Zhao X.Y.
        • Meng Z.X.
        • Kern M.
        • Dietrich A.
        • Chen Z.
        • et al.
        The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis.
        Nat Med. 2014; 20: 1436-1443
        • Yoneshiro T.
        • Aita S.
        • Matsushita M.
        • Kayahara T.
        • Kameya T.
        • Kawai Y.
        • et al.
        Recruited brown adipose tissue as an antiobesity agent in humans.
        J Clin Invest. 2013; 123: 3404-3408
        • Chen Y.-C.I.
        • Cypess A.M.
        • Chen Y.-C.
        • Palmer M.
        • Kolodny G.
        • Kahn C.R.
        • et al.
        Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging.
        J Nucl Med. 2013; 54: 1584-1587
        • Reddy N.L.
        • Jones T.A.
        • Wayte S.C.
        • Adesanya O.
        • Sankar S.
        • Yeo Y.C.
        • et al.
        Identification of brown adipose tissue using MR imaging in a human adult with histological and immunohistochemical confirmation.
        J Clin Endocrinol Metab. 2014; 99: E117-E121