title: p-Cresyl sulfate promotes insulin resistance associated with CKD.
abstract: The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.
authors.affiliation: Hospices Civils de Lyon, Department of Nephrology, Hôpital E Herriot, Lyon, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Koppe
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Pillon
authors.forename: Roxane E
authors.initials: RE
authors.lastname: Vella
authors.forename: Marine L
authors.initials: ML
authors.lastname: Croze
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Pelletier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chambert
authors.forename: Ziad
authors.initials: Z
authors.lastname: Massy
authors.forename: Griet
authors.initials: G
authors.lastname: Glorieux
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
authors.forename: Yann
authors.initials: Y
authors.lastname: Dugenet
authors.forename: Hédi A
authors.initials: HA
authors.lastname: Soula
authors.forename: Denis
authors.initials: D
authors.lastname: Fouque
authors.forename: Christophe O
authors.initials: CO
authors.lastname: Soulage
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D052436:Adipose Tissue, White / Q000187:drug effects; D000818:Animals; D003408:Cresols / Q000008:administration & dosage / Q000378:metabolism*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006937:Hypercholesterolemia / Q000139:chemically induced; D006943:Hyperglycemia / Q000139:chemically induced; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D056692:Prebiotics; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013463:Sulfuric Acid Esters; D014511:Uremia / Q000178:diet therapy
chemical_list: D003408:Cresols; D007328:Insulin; D056692:Prebiotics; D013463:Sulfuric Acid Esters; C032538:4-cresol; C408690:4-cresol sulfate; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose