title: Pancreastatin-dependent inflammatory signaling mediates obesity-induced insulin resistance.
abstract: Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A-derived peptide pancreastatin (PST: CHGA(273-301)) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-NΔ3: CHGA(276-301)), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.
authors.affiliation: VA San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Gautam K
authors.initials: GK
authors.lastname: Bandyopadhyay
authors.affiliation: VA San Diego Healthcare System, San Diego, CA.
authors.forename: Minh
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Ennio
authors.initials: E
authors.lastname: Avolio
authors.affiliation: VA San Diego Healthcare System, San Diego, CA.
authors.forename: Jawed A
authors.initials: JA
authors.lastname: Siddiqui
authors.affiliation: Central Drug Research Institute, Lucknow, India.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wollam
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Christine U
authors.initials: CU
authors.lastname: Vu
authors.affiliation: VA San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
authors.affiliation: VA San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, San Diego, CA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
authors.affiliation: VA San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, San Diego, CA smahata@ucsd.edu.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis / Q000276:immunology; D053379:Chromogranin A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D010187:Pancreatic Hormones / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015434:Panniculitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000276:immunology / Q000378:metabolism
chemical_list: D053379:Chromogranin A; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D010187:Pancreatic Hormones; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C506155:chromogranin A, mouse; C071102:pancreastatin-52