Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang, Haihua; Yang, Linghai

doi:10.1530/jme-15-0316

Cited by 140 publications

(98 citation statements)

References 179 publications

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“…The Webgestalt tool did not identify any over-represented pathways among these 16 genes associated with insulin sensitivity as compared to all analyzed genes. However, specific genes reported to be phenotypically linked to adipose functions and potentially involved in the regulation of insulin sensitivity include ACVR1C , which inhibits lipolysis [33], PRKAR2A which comprises a subunit of protein kinase A [34], SEMA3E which regulates adipose inflammation [35], and SKP2 [36] which controls adipocyte number.…”

Section: Resultsmentioning

confidence: 99%

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

et al. 2017

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Although the mechanisms linking obesity to insulin resistance (IR) and type 2 diabetes (T2D) are not entirely understood, it is likely that alterations of adipose tissue function are involved. The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin resistant (OIR) or sensitive (OIS) adipocytes. Insulin sensitivity was first determined by measuring lipogenesis in isolated adipocytes from abdominal subcutaneous white adipose tissue (WAT) in a large observational study. Lipogenesis was measured under conditions where glucose transport was the rate limiting step and reflects in vivo insulin sensitivity. We then performed microarray-based transcriptome profiling on subcutaneous WAT specimen from a subgroup of 9 lean, 21 OIS and 18 obese OIR women. We could identify 432 genes that were differentially expressed between the OIR and OIS group (FDR ≤5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include genes such as SLC2A4, AKT2, as well as genes coding for enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 encoding a transcription factor and SLC25A10 encoding a dicarboxylate carrier, were selected for functional evaluation in adipocytes differentiated in vitro. Knockdown of KLF15 and SLC25A10 using siRNA inhibited insulin-stimulated lipogenesis in adipocytes. Transcriptome profiling of siRNA-treated cells suggested that KLF15 might control insulin sensitivity by influencing expression of PPARG, PXMP2, AQP7, LPL and genes in the mitochondrial respiratory chain. Knockdown of SLC25A10 had only modest impact on the transcriptome, suggesting that it might directly influence insulin sensitivity in adipocytes independently of transcription due to its important role in fatty acid synthesis. In summary, this study identifies novel genes associated with insulin sensitivity in adipocytes in women independently of obesity. KFL15 and SLC25A10 are inhibitors of insulin-stimulated lipogenesis under conditions when glucose transport is the rate limiting step.

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Section: Resultsmentioning

confidence: 99%

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

et al. 2017

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“…The PKA/cAMP signaling pathway regulates glucose and lipid metabolism, proliferation, and hepatocyte survival. (43–45) The PKA catalytic subunit, PRKACA , is commonly activated by mutations in adrenocortical tumors(32) and recurrent translocations in fibrolamellar HCC. (32,46) β-adrenergic receptors activate PKA/cAMP signaling in many cell types including hepatocytes and regulate many cancer-relevant cellular processes including growth, metabolism, DNA damage repair, cell motility, survival, and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors

et al. 2017

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Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance.

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“…Expression of these enzymes is controlled via hormonal modulation of transcription factors and coactivators (7). Abundant evidence indicates that the cyclic AMP (cAMP) signaling pathway is central to the hormonal control of gluconeogenesis (8), and cAMP-responsive element (CRE)-binding protein (CREB) is a particularly important effector of the cAMP pathway in liver (9,10). Both Pck1 and G6pc genes encoding PEPCK and G6Pase, respectively, possess CRE in their promoter regions and binding of CREB to CRE increases the transcriptional activity of these genes.…”

Section: Modulation Of Hepatic Nf-y Expression Maymentioning

confidence: 99%

Regulation of hepatic gluconeogenesis by nuclear factor Y transcription factor in mice

Zhang

Guan

Yin

et al. 2018

Journal of Biological Chemistry

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Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Cited by 140 publications

References 179 publications

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

Global transcriptome profiling identifies KLF15 and SLC25A10 as modifiers of adipocytes insulin sensitivity in obese women

Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors

Regulation of hepatic gluconeogenesis by nuclear factor Y transcription factor in mice

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