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 ) 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-ND3: 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.The chromogranin A (human CHGA/mouse Chga) proprotein (1-4) undergoes proteolysis and gives rise to bioactive peptides including the antihypertensive catestatin (CHGA 352-372 ) (5-8) and the diabetogenic pancreastatin (PST: CHGA 250-301 ) (9-12). We have shown that Chgadeficient mice (Chga-KO) are obese, hyperadrenergic, and hypertensive. They display elevated levels of circulating leptin and catecholamines but lower levels of interleukin (IL)-6 and Mcp-1 (11,13-16). Despite these abnormalities, Chga-KO mice exhibit enhanced insulin sensitivity (11), a phenotype masked by supplementing PST. PST regulates hepatic insulin signaling through conventional (c) PKC and Srebp-1c (11). Increased plasma PST levels in diabetic populations correlate with insulin resistance (10). Similarly, increased circulating levels of PST in diet-induced obesity (DIO) and db/ db mice are associated with insulin resistance. Despite high levels of plasma leptin and catecholamines, Chga-KO mice are obese owing to peripheral leptin and catecholamine resistance (17).Since normal chow diet (NCD)-fed Chga-KO mice displayed increased insulin sensitivity (11), we hypothesized that Chga-KO mice may be able to maintain insulin sensitivity when exposed to the dysglycemic stress of a highfat diet (HFD). The hallmarks of insulin resistance in DIO mice are obesity, hyperinsulinemia, and increased inflammation (18)(19)(20)(21)(22). Suppression of inflammation in DIO mice can improve insulin sensitivity (23-25). For example, rosiglitazone can improve inflammation and insulin sensitivity in DIO mice without reducing obesity significantly (23-25). Chga-KO mice are...

Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo

“…Consistent with an enhanced metabolic burden of ATP-dependent vesicular transport in Chga -KO mice, we found evidence for profound alteration in subcellular morphology of organelles involved in energy metabolism, including mitochondria, ER and GC. The ultrastructural findings correlate well with the pathophysiological findings reported earlier in Chga -KO mice (Bandyopadhyay et al 2015; Gayen et al 2009a, b; Mahapatra et al 2005). We also observed greatly enhanced glucose uptake and utilization in Chga -KO mice, consistent with increased metabolic burden on the chromaffin cell in the absence of CgA expression in the adrenal medulla.…”

“…One of the main functions of insulin is to stimulate glycogenesis and inhibit glycogenolysis. We have previously reported Chga -KO mice as being hypertensive, hyperadrenergic and sensitive to insulin (Bandyopadhyay et al 2015; Gayen et al 2009a, b; Mahapatra et al 2005). Therefore, increased glycogen granules in the adrenal medulla of Chga -KO mice may be a reflection of heightened insulin sensitivity in Chga -KO mice (Bandyopadhyay et al 2015; Gayen et al 2009b).…”

“…The extracellular function of CgA includes the generation of bioactive peptides, such as the insulin-regulatory hormone pancreastatin (Bandyopadhyay et al 2015; Gayen et al 2009b; Sanchez-Margalet et al 2010; Tatemoto et al 1986), the vasodilating and cardioprotective vasostatin (Aardal et al 1993; Tota et al 2008), the anti-adrenergic (Mahata et al 2003; Mahata, et al 2010; Mahata et al 1997), anti-hypertensive (Mahapatra et al 2005), anti-obesity (Bandyopadhyay et al 2012), proangiogenic (Theurl et al 2010) and cardioprotective catestatin (Angelone et al 2008; Mahata et al 2010) and the pro-adrenergic serpinin (Tota et al 2012). The intracellular function of CgA includes the initiation and regulation of DCV biogenesis and sequestration of hormones in neuroendocrine cells (Elias et al 2012; Iacangelo and Eiden 1995; Kim et al 2001; Taupenot et al 2002).…”

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

“…Glucose-lowering effect of berberine metabolites on high-fat-diet -induced hyperglycemia in mice The animal model of high-fat-diet (HFD)-induced hyperglycemia or insulin resistance has been widely used in the assessment of glucose-lowering effects [28,29] . After 9 weeks of continuous feeding with HFD, the glucose level in the plasma of the HFD mice was significantly elevated (12.17±1.70 vs 6.52±1.83 mmol/L, P<0.01).…”

Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice

“…) tissue type (stomach, duodenum, jejunum, ileum, ascending colon, or descending colon); and (Bandyopadhyay et al. ) the animal the sample was obtained from. Since multiple tissue samples were collected from each individual animal, the animal was considered as a random effect.…”