title: Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR-δ agonism correlates with impaired NLRP3 inflammasome activation.
abstract: Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity ("diabesity") remains unclear. Peroxisome-proliferator activated receptor (PPAR)-δ agonists have never been tested in models of sugar-induced metabolic abnormalities. This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15% wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-δ agonist GW0742 (1 mg/kg/day for 16 weeks) in this condition. HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation. In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events. In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1β production. All of the above effects of HFCS-55 were attenuated by the specific PPAR-δ agonist GW0742. Thus, we demonstrate for the first time that the specific PPAR-δ agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney).
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy. massimo.collino@unito.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.forename: Muhammed M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D004195:Disease Models, Animal; D005631:Fructokinases / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects; D005947:Glucose / Q000008:administration & dosage / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047495:PPAR gamma / Q000819:agonists*; D012639:Seeds / Q000737:chemistry; D013844:Thiazoles / Q000627:therapeutic use; D003313:Zea mays / Q000737:chemistry; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D002352:Carrier Proteins; D004040:Dietary Carbohydrates; D005631:Fructokinases; D005632:Fructose; D005947:Glucose; D007004:Hypoglycemic Agents; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047495:PPAR gamma; D013844:Thiazoles; C492716:Nlrp3 protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C021475:ketohexokinase