title: Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation.
abstract: Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-α, IL-1β, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties.
authors.affiliation: Department of Surgery (H.D., X.Y., D.-s.K., A.S., K.D.C., D.B.A., H.Wa.), Medical University of South Carolina, Charleston, South Carolina 29425; Departments of Endocrinology, Diabetes, and Metabolism (H.H., Y.-B.K.) and Surgery (Y.Y., L.E.O.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; Department of Medicine (H.Wu), Section of Endocrinology, Tulane University, New Orleans, Louisiana 70112 and Department of Kinesiology and Physiology (H.H.), East Carolina University, Greenville, North Carolina 27858.
authors.forename: Huansheng
authors.initials: H
authors.lastname: Dong
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.forename: Xinxu
authors.initials: X
authors.lastname: Yun
authors.forename: Do-sung
authors.initials: DS
authors.lastname: Kim
authors.forename: Yinan
authors.initials: Y
authors.lastname: Yue
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
authors.forename: Alton
authors.initials: A
authors.lastname: Sutter
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: David B
authors.initials: DB
authors.lastname: Adams
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D001835:Body Weight; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005951:Glucose Tolerance Test; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D011489:Protein Denaturation; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D007328:Insulin; D020738:Leptin; D008565:Membrane Proteins; D054411:Receptors, Leptin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001663:Bilirubin