title: Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance.
abstract: Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = -0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland Children's Research Centre, University Children's Hospital, Zurich, Switzerland daniel.konrad@kispi.uzh.ch stephan.wueest@usz.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wueest
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
authors.forename: Flurin
authors.initials: F
authors.lastname: Item
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland Children's Research Centre, University Children's Hospital, Zurich, Switzerland Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Fabrizio C
authors.initials: FC
authors.lastname: Lucchini
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
authors.forename: Tenagne D
authors.initials: TD
authors.lastname: Challa
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, U.K.
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland Children's Research Centre, University Children's Hospital, Zurich, Switzerland Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland daniel.konrad@kispi.uzh.ch stephan.wueest@usz.ch.
authors.forename: Daniel
authors.initials: D
authors.lastname: Konrad
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D050822:Cytokine Receptor gp130 / Q000235:genetics* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008066:Lipolysis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D009852:Omentum / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050151:Subcutaneous Fat / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; C494200:Il6st protein, mouse; D015850:Interleukin-6; D050822:Cytokine Receptor gp130