Gene enrichment analysis was done using the hypergeometric distribution with BenjaminiCHochberg correction. Supplementary Material Supplementary FileClick here to view.(590K, pdf) Supplementary FileClick here to view.(199K, pdf) Supplementary FileClick here to view.(202K, pdf) Acknowledgments We thank George Kenty for running the microarrays and members of our group for fruitful discussions. is required for the compensatory hyperglucagonemia and -cell proliferation following treatment with glucagon receptor antagonists. mice (16) and humans with a nonfunctional glucagon receptor (17). The adverse side effects of GRAs present a practical need to understand the compensatory response of -cells and raise basic questions regarding the control over -cell proliferation. Surprisingly, nearly full ablation of -cells does not increase -cell proliferation or alter circulating glucagon levels (18), CDK-IN-2 raising the hypothesis that, unlike -cells, hormonal hypersecretion alone does not promote proliferation (19, 20). Rather, a reduction of glucagon signaling, either by GRA treatment or receptor knockout, feeds back to induce -cell proliferation (21). In this study, we treated mice with a GRA to identify secreted factors leading to -cell proliferation and hyperglucagonemia. We find that Angptl4 is up-regulated in white adipose tissue (WAT) and in plasma following GRA treatment. Angptl4 is a multifunctional secreted protein that is cleaved into an N-terminal part containing a coil-coil domain that inhibits lipoprotein lipase (LPL) and a C-terminal part with a fibrinogen-like domain that affects vasculature (22). The LPL inhibitory N-terminal fragment constitutes most of the blood-borne CDK-IN-2 fraction of Angptl4 and can act in a paracrine and endocrine manner (23, 24). Angptl4 is a glucocorticoid and Ppar target gene, up-regulated during fasting and exercise and expressed in many tissues, but primarily in WAT in mice. Local up-regulation of Angptl4 expression diverts triglyceride utilization for fatty acid oxidation to other tissues (25C30). Knockout and overexpression of lead to decreased or increased triglyceride levels, respectively, in mice (31), and mutations in the human gene are associated with lower triglyceride levels in the blood (32). We show that treatment with recombinant Angptl4 protein specifically increases -cell proliferation rates of young and old mice without increasing glucagon levels. Activation of Ppar up-regulates expression in WAT but not in the liver and results in increased -cell proliferation. Ppar activation increased hepatic but did not raise -cell proliferation rates. Notably, GRA treatment led to Ppar activation in WAT but did not activate Ppar in liver. Caloric restriction, which increases plasma Angptl4 levels (29), led to up-regulation of WAT but not CDK-IN-2 liver expression and increased -cell proliferation. mice have a normal islet morphology and -cell proliferation rate. GRA treatment improves glycemia of diet-induced obese (DIO) mice without increasing glucagon CRE-BPA levels or -cell proliferation. In all, the data show that Angplt4 is sufficient to induce -cell proliferation and is required for the adverse response of -cells to GRA treatment. Results Glucagon Receptor Antagonism Leads to Hyperglucagonemia and an Increase in -Cell Proliferation. We generated a model of an acute treatment with a GRA to identify secreted factors leading to -cell replication and hyperglucagonemia. Osmotic pumps were used to administer either PBS (control) or the GRA des-His1-[Glu9)-glucagon(1C29) amide for 6 d in 8-wk-old male mice (33, 34). As expected, administration of this GRA led to a lower fasting glycemia, a CDK-IN-2 reduction in glucose production following i.p. injection of glucagon, and an increase in plasma glucagon and triglyceride levels (Fig. 1 = 7C8 per group; = 0.03. (and = 4C5 per group; = 0.02 in all three cases. (= 5 and 7; = 0.003. (= 5; = 0.008. (= 10. = 0.003 for -cells; = 0.17 for -cells. (= 0.02; * 0.05; ** 0.01. GRA administration caused a twofold increase in the fraction of proliferating -cells, rising from 0.75 to 1.5% without changing -cell proliferation (Fig. 1 and Fig. S1). EdU staining shows an increase in the fraction of new -cells following GRA treatment in both the head and the tail of the pancreas (Fig. 1and Fig. S1), confirming the previously reported increase in -cell proliferation in GRA-treated mice (13C15). There was also a small increase in the fraction of L-cells in the ileum of GRA-treated mice (Fig. S1) (35). IL6R signaling was shown to be required for -cell proliferation in a high-fat-diet model and after duct ligation (36, 37); however, we did not detect nuclear pStat3 in -cells following GRA treatment. Open in a separate window Fig. S1. Supporting figure for Figs. 1 and 2. (= 10. = 0.003 for -cells; = 0.17 for -cells. (= 5. = 0.02 (head), 0.07 (tail), and 0.02 (whole pancreas). (= 0.03; = 5C7. (was down-regulated and amino acid metabolism altered (Dataset S1). Analysis of overrepresented gene ontology terms in WAT pointed to changes in lipoprotein handling in the extracellular space (Fig. 2and Dataset S2) (40). Open in a separate window Fig. 2. Gene expression analysis in white adipose tissue following GRA identifies up-regulation of value 0.05 were chosen for this analysis. ( .
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