Metabolic interplay between white, beige, brown adipocytes and the liver  Ludger Scheja, Joerg Heeren  Journal of Hepatology  Volume 64, Issue 5, Pages 1176-1186 (May 2016) DOI: 10.1016/j.jhep.2016.01.025 Copyright © 2016 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Overview of the metabolic and hormonal interplay between liver and adipose tissues in the context of obesity and adaptive thermogenesis. (A) In lean conditions, white adipocytes release fatty acids that are used by hepatocytes for either VLDL production or especially after prolonged fasting for beta-oxidation and production of ketone bodies such as hydroxybutyrate. Adiponectin and leptin secreted by white adipocytes influence this process by stimulating hepatic beta-oxidation. One of the main metabolic function of the liver is to distribute energy to other organs by secreting TG-rich VLDL. Liver-derived apolipoproteins (Apos) and angiopoetin-like proteins (ANGPTLs) regulate the organ-specific delivery of VLDL-TG as well as dietary lipids that are transported by intestinal-derived chylomicrons (CM). Liver-derived lipid metabolites (hydroxybutyrate as well as bile acids) are known to act in an anti-inflammatory and insulin-sensitizing fashion in white adipose tissue (WAT). In addition, bile acids stimulate thermogenesis in brown adipose tissue (BAT). An endocrine role for some factors including hepatic FGF21 for adipose tissue metabolism such as glucose uptake and lipolysis has been proposed; however, direct experimental evidence for such a role has not been provided yet. (B) In obesity, insulin resistant white adipocytes release higher amounts of fatty acids whereas adiponectin secretion is decreased (indicated by the arrows). In addition, hypertrophic adipocytes and tissue-resident macrophages in WAT secrete pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin 6 (IL6). Both increased fatty flux and altered adipokine levels contribute to elevated hepatic lipid content, inflammation and the development of non-alcoholic fatty liver disease. This condition is associated with the induction of pro-inflammatory genes such as fetuin-A and apolipoprotein C3 triggering metabolic alterations such as peripheral insulin resistance and hyperlipidemia, respectively. (C) In response to cold exposure, thermogenic brown and beige adipocytes produce heat by oxidizing fatty acids delivered by VLDL or chylomicrons as well as glucose (not shown) in order to keep body temperature. Under these conditions, sufficient fatty acids flux to the liver is maintained by increased lipolysis in WAT. In addition to lipoproteins, the liver produces bile acids that stimulate adaptive thermogenesis and promote the browning of white adipose tissue. Next to their role in energy utilization, brown adipocytes improve metabolic parameters by releasing IL6, IGF1 and NRG4. Whereas IL6 enhances glucose disposal into white adipocytes and muscle cells (not shown in the model), IGF1 suppresses hepatic glucose production and NRG4 inhibits DNL in the liver, indicating a shift of energy-consuming processes to metabolic active organs in the periphery. Journal of Hepatology 2016 64, 1176-1186DOI: (10.1016/j.jhep.2016.01.025) Copyright © 2016 European Association for the Study of the Liver Terms and Conditions

Journal of Hepatology 2016 64, 1176-1186DOI: (10. 1016/j. jhep. 2016 Copyright © 2016 European Association for the Study of the Liver Terms and Conditions