title: Adipocytes as a Link Between Gut Microbiota-Derived Flagellin and Hepatocyte Fat Accumulation.
abstract: While the role of both elevated levels of circulating bacterial cell wall components and adipose tissue in hepatic fat accumulation has been recognized, it has not been considered that the bacterial components-recognizing adipose tissue receptors contribute to the hepatic fat content. In this study we found that the expression of adipose tissue bacterial flagellin (FLG)-recognizing Toll-like receptor (TLR) 5 associated with liver fat content (r = 0.699, p = 0.003) and insulin sensitivity (r = -0.529, p = 0.016) in humans (n = 23). No such associations were found for lipopolysaccharides (LPS)-recognizing TLR4. To study the underlying molecular mechanisms of these associations, human HepG2 hepatoma cells were exposed in vitro to the conditioned culture media derived from FLG or LPS-challenged human adipocytes. The adipocyte-mediated effects were also compared to the effects of direct HepG2 exposure to FLG and LPS. We found that the media derived from FLG-treated adipocytes stimulated fat accumulation in HepG2 cells, whereas either media derived from LPS-treated adipocytes or direct FLG or LPS exposure did not. This is likely due to that FLG-treatment of adipocytes increased lipolysis and secretion of glycerol, which is known to serve a substrate for triglyceride synthesis in hepatocytes. Similarly, only FLG-media significantly decreased insulin signaling-related Akt phosphorylation, IRS1 expression and mitochondrial respiratory chain ATP5A. In conclusion, our results suggest that the FLG-induced TLR5 activation in adipocytes increases glycerol secretion from adipocytes and decreases insulin signaling and mitochondrial functions, and increases fat accumulation in hepatocytes. These mechanisms could, at least partly, explain the adipose tissue TLR5 expression associated with liver fat content in humans.
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.|Department of Clinical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Munukka
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Wiklund
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Partanen
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Sakari
authors.initials: S
authors.lastname: Välimäki
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Eija K
authors.initials: EK
authors.lastname: Laakkonen
authors.affiliation: LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Lehti
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovzsky
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.|Department of Physical Education, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Sulin
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Clinical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Pentti
authors.initials: P
authors.lastname: Huovinen
authors.affiliation: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.|Department of Clinical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Pekkala
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D005223:Fats / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D005408:Flagellin / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D064307:Microbiota; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D005223:Fats; D000091344:Filaggrin Proteins; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D005408:Flagellin