title: Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice.
abstract: Sleep fragmentation (SF), a frequent occurrence in multiple sleep and other diseases leads to increased food intake and insulin resistance via increased macrophage activation and inflammation in visceral white adipose tissue (VWAT). Free fatty acid receptor 4 (FFA4) is reduced in pediatric sleep apnea patients and FFA4 agonists have been proposed in the treatment of obesity and metabolic dysfunction.
  
  
  
  Male mice were subjected to SF exposures for 6 weeks, and treated during the last 2 weeks with either TUG891, a potent and selective FFA4 agonist, or vehicle (Veh). Glucose and insulin tolerance tests and VWAT insulin sensitivity tests were conducted (phosphorylated Akt/total Akt), along with flow cytometric assessments of VWAT macrophage polarity, and T-cell lymphocyte subsets.
  
  
  
  SF-TUG891 mice showed reduction in food consumption, weight gain and VWAT mass. Furthermore, TUG891 treatment ameliorated glucose tolerance test and insulin tolerance test responses and increased VWAT p-Akt/Akt responses to insulin. Increases in M1/M2 macrophages and decreased Treg counts in VWAT associated with SF were markedly improved by TUG891, and VWAT macrophages from TUG891-treated mice had markedly attenuated insulin resistance effects on naïve cultured adipocytes.
  
  
  
  Treatment with an FFA4 agonist reverses SF-induced food intake increases and gains in body weight, and significantly attenuates VWAT inflammation and insulin resistance. Thus, interventional dietary or pharmaceutical strategies aimed at increasing FFA4 activity may serve as potentially useful adjunctive therapies for sleep disorders accompanied by metabolic morbidity.
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gozal
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA.
authors.forename: I
authors.initials: I
authors.lastname: Almendros
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Khalyfa
authors.affiliation: Departments of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Shimpukade
authors.affiliation: Departments of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Ulven
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012892:Sleep Deprivation / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C585065:3-(4-((4-fluoro-4'-methyl-(1,1'-biphenyl)-2-yl)methoxy)phenyl)propanoic acid; D001713:Biphenyl Compounds; C498007:FFAR4 protein, mouse; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled