Pancreastatin-Dependent Inflammatory Signaling Mediates Obesity-Induced Insulin Resistance

Bandyopadhyay, Gautam; Lu, Minh Lon; Avolio, Ennio; Siddiqui, Jawed A.; Gayen, Jiaur R.; Wollam, Joshua; Vu, Christine U.; Chi, Nai‐Wen; O’Connor, Daniel T.; Mahata, Sushil K.

doi:10.2337/db13-1747

Cited by 64 publications

(78 citation statements)

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“…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.…”

Section: Discussionsupporting

confidence: 90%

“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30–40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100–200 nm) than in WT mice (200–350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…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).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg· kg -1 ·d -1 , ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg· kg -1 ·d -1 ) or BRB (25 mg· kg -1 ·d -1 ). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 μmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

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“…) 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.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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The gastrointestinal (GI) tract can have significant impact on the regulation of the whole‐body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analysis in different parts of the GI tract of two obese mouse models: ob/ob and high‐fat diet (HFD) fed mice. Compared to their lean controls, significant changes in the gene expression were observed in both obese mouse groups in the stomach (ob/ob: 959; HFD: 542). In addition, these changes were quantitatively much higher than in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes, and insulin resistance. In addition, the gene expression profiles strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity in murine models extensively used in research.

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Pancreastatin-Dependent Inflammatory Signaling Mediates Obesity-Induced Insulin Resistance

Cited by 64 publications

References 50 publications

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

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

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

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

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