Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Serrano, Rosario; Villar, Margarita; Martı́nez, Carmen; Carrascosa, Jóse M.; Gallardo, Nilda; Andrés, Antonio

doi:10.1677/jme.1.01635

Cited by 51 publications

(36 citation statements)

References 42 publications

(28 reference statements)

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“…IR-A was the predominant isoform in the undifferentiated, cycling IESCs and rapidly dividing progenitors in the crypt, whereas IR-B expression was increased in Sox9-EGFP High cells enriched for post-mitotic EEC and Sox9-EGFP Negative IECs enriched for other post-mitotic, differentiated lineages, including enterocytes. Our findings are consistent with studies in other tissues where IR-A levels were higher in progenitor cells, including white pre-adipocytes, osteoblast precursors and neural progenitors compared with differentiated cells (Avnet et al, 2012;Serrano et al, 2005;Ziegler et al, 2012).…”

Section: Discussionsupporting

confidence: 92%

“…Importantly, our studies provide novel information that the increase in total IR reflects a significant and predominant increase in levels of IR-B mRNA and protein. This is consistent with other studies in breast, bone and adipose tissue showing that IR-B expression is enhanced following differentiation of progenitors or progenitor cell lines (Avnet et al, 2012;Berlato and Doppler, 2009;Entingh et al, 2003;Rowzee et al, 2009;Serrano et al, 2005). The increased level of IR-B in post-confluent differentiated Caco-2 cells is functional, as indicated by enhanced insulin-mediated IR-B tyrosine phosphorylation.…”

Section: Discussionsupporting

confidence: 92%

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Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

Andres

Simmons

Mah

et al. 2013

Journal of Cell Science

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SummaryDespite evidence for the impact of insulin on intestinal epithelial physiology and pathophysiology, the expression patterns, roles, and regulation of insulin receptor (IR) and IR isoforms in the intestinal epithelium are not well characterized. IR-A is thought to mediate the proliferative effects of insulin or insulin growth factors (IGFs) in fetal or cancer cells. IR-B is considered to be the metabolic receptor for insulin in specialized tissues. This study used a novel Sox9-EGFP reporter mouse that permits isolation of intestinal epithelial stem cells (IESCs), progenitors, enteroendocrine cells and differentiated lineages, the ApcMin/+ mouse model of precancerous adenoma and normal human intestinal and colorectal cancer (CRC) cell lines. We tested the hypothesis that there is differential expression of IR-A or IR-B in stem and tumor cells versus differentiated intestinal epithelial cells (IECs) and that IR-B impacts cell proliferation. Our findings provide evidence that IR-B expression is significantly lower in highly proliferative IESCs and progenitor cells versus post-mitotic, differentiated IECs and in subconfluent and undifferentiated versus differentiated Caco-2 cells. IR-B is also reduced in Apc Min/+ tumors and highly tumorigenic CRC cells. These differences in IR-B were accompanied by altered levels of mRNAs encoding muscleblind-like 2 (MBNL2), a known regulator of IR alternative splicing. Forced IR-B expression in subconfluent and undifferentiated Caco-2 cells reduced proliferation and increased biomarkers of differentiation. Our findings indicate that the impact of insulin on different cell types in the intestinal epithelium might differ depending on relative IR-B: IR-A expression levels and provide new evidence for the roles of IR-B to limit proliferation of CRC cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

Andres

Simmons

Mah

et al. 2013

Journal of Cell Science

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“…Upon binding to its receptor, insulin induces autophosphorylation of tyrosine residues within the B subunit of the receptor. This increases tyrosine kinase activity of the InsR and phosphorylates the cellular substrates [18,19].…”

Section: Discussionmentioning

confidence: 99%

High Insulin Concentrations Repress Insulin Receptor Gene Expression in Calf Hepatocytes Cultured <i>in Vitro</i>

Zhang

Liu

et al. 2011

Cell Physiol Biochem

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The major role of insulin and the insulin receptor (InsR) in the liver is to mediate glucose uptake into hepatocytes to synthesize glycogen and to maintain blood glucose homeostasis. In this study, we investigated the effects of high insulin concentrations on InsR gene expression in calf hepatocytes cultured in vitro. After the cells were cultured for 72 h, insulin was added to the culture solution at final concentrations of 0, 1, 10, 100 or 1000 nM. InsR mRNA expression was determined by semi-quantitative RT-PCR. The results showed that InsR mRNA expression in hepatocytes, adjusted for β-actin expression, decreased dose dependently with increasing insulin concentration. InsR mRNA expression was similar at 1 and 10 nM insulin, but was significantly lower than that in the control. InsR expression was similar at 100 and 1000 nM insulin, but was significantly lower than that in the control, 1 and 10 nM insulin groups. These data suggest that high concentrations of insulin significantly repress InsR mRNA expression in calf hepatocytes, and this inhibition occurs in a dose-dependent manner. Further studies are needed to investigate the mechanisms underlying these effects of insulin.

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“…The IR occurs in WAT as two alternatively spliced isoforms, IR-A (exon 11Ϫ) and IR-B (exon 11ϩ) (34). To quantify the differential expression of IR-A and IR-B, specific primers were used in each case.…”

Section: Effects Of Central Leptin On Ir Irs-1 and Glut4 Mrna And Tmentioning

confidence: 99%

Regulation of Insulin-Stimulated Glucose Uptake in Rat White Adipose Tissue upon Chronic Central Leptin Infusion: Effects on Adiposity

et al. 2011

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Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 g/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [ 3 H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity. (Endocrinology 152: 1366 -1377, 2011)

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Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Cited by 51 publications

References 42 publications

Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

High Insulin Concentrations Repress Insulin Receptor Gene Expression in Calf Hepatocytes Cultured <i>in Vitro</i>

Regulation of Insulin-Stimulated Glucose Uptake in Rat White Adipose Tissue upon Chronic Central Leptin Infusion: Effects on Adiposity

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