Revised Manuscript DB13-1747R2 Pancreastatin-dependent inflammatory signaling mediates obesity-induced insulin resistance

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: CHGA273-301), 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 pro-inflammatory genes and upregulation of antiinflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced pro-inflammatory 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: CHGA276-301), lacking PST activity, simulated the KO phenotype by sensitizing WTDIO 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. Page 2 of 37 Diabetes