Pancreastatin-dependent inflammatory signaling mediates obesity-induced insulin resistance
- Gautam K. Bandyopadhyay1,2,
- Minh Lu1,
- Ennio Avolio2,
- Jawed A. Siddiqui1,
- Jiaur R. Gayen3,
- Joshua Wollam2,
- Christine U. Vu2,
- Nai-Wen Chi1,2,
- Daniel T. O’Connor1,2 and
- Sushil K. Mahata1,2⇑
- 1From the VA San Diego Healthcare System, San Diego, California, USA;
- 2Department of Medicine, University of California, San Diego, California, USA;
- 3Central Drug Research Institute, Lucknow, India
- Corresponding author: Sushil K. Mahata, E-mail:
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 anti-inflammatory 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 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.
- Received November 15, 2013.
- Accepted July 12, 2014.
- © 2014 by the American Diabetes Association.
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