2 41of insulin signaling (Arap et al. 2004 ; Delpino and Castelli 2002 ; Misra et al. 2006 ;
Misra and Pizzo 2010 ; Shani et al. 2008 ; Wang et al. 2009 ; Zhang et al. 2010 ).
Although, ligand-affinity experiments show some evidence for a GPCR-PST bind-
ing, it is conceivable that an additional high-affinity receptor for PST should exist.
In conclusion, GRP78, could be a probable additional mechanism of PST cross-talk
with insulin receptor whereby PST may interfere with insulin action.
.
5 PST and Inflammation Signaling
Studies in chromogranin A knockout-mice have brought to light the development of
an anti-inflammatory environment in adipose tissue, which involves the downregu-
lation of pro-inflammatory genes and cytokines and an upregulation of inflamma-
tory genes in WAT and peritoneal macrophages. In parallel to anti-inflammatory
events, the insulin resistance produced by high fat diet was prevented by CGA gene
ablation. Thus, anti-inflammatory environment and enhanced insulin sensitivity,
have been reversed by PST administration. Furthermore, it has been demonstrated
that the insulin resistance in obese individuals is manifested only if PST is present,
while in its absence obesity dissociates from it. The anti-inflammatory environment
keeps a close relationship with altered PI3-K/Akt /Foxo1 signaling in CGA-KO
individuals, suggesting that this may be the underlying mechanism in the pro-
inflammatory activity of PST. By contrast, application of the truncated, variant of
PST peptide (PST v1) simulates KO anti-inflammatory phenotype in WT obese
individuals and simultaneously improving insulin sensitivity. Thus it seems that
PSTv1 could operate as a PST competitive inhibitor, but further studies will be nec-
essary to prove whether its administration to insulin resistant subjects could improve
insulin sensitivity by reducing PST induced inflammation (Bandyopadhyay et al.
2015 ).
6 PST as a Stress Peptide
Considering the variety of biological actions ascribed to PST, the physiological role
of this peptide could be a local modulator of secretion in glands where this peptide
is actually processed and secreted. Hence, we can speculate that PST operates as an
autocrine and paracrine regulatory peptide of endocrine and exocrine secretion
attributing a significant physiological role for PST
The fact is that, PST levels are increased under the stressful stimuli when CGA
is co-secreted with catecholamines from the sympathetic system. Higher PST levels
leads to reduced insulin sensitivity in the liver and adipose tissues, which results in
increased glycogenolysis in the liver and lipolysis in the adipose tissue, providing
an extra energy to the whole organism in stressful conditions (Sanchez-Margalet
Action and Mechanisms of Action of the Chromogranin A Derived Peptide Pancreastatin