Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2–/– Mice

Suzuki, Ryo; Tobe, Kazuyuki; Aoyama, Masashi; Inoue, Atsushi; Sakamoto, Kei; Yamauchi, Toshimasa; Kamon, Junji; Kubota, Naoto; Terauchi, Yasuo; Yoshimatsu, Hironobu; Matsuhisa, Munehide; Nagasaka, Shoichiro; Ogata, Hiroyasu; Tokuyama, Kumpei; Nagai, Ryozo; Kadowaki, Takashi

doi:10.1074/jbc.m311956200

Cited by 59 publications

(55 citation statements)

References 61 publications

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“…To verify the hypothesis, we investigated the gene expression in the WAT of Irs2 Ϫ/Ϫ mice and ob/ob mice after continuous intracerebroventricular infusion of leptin. Leptin infusion at a rate of 300 ng/h yielded lean Irs2 Ϫ/Ϫ mice and overcame their leptin resistance as previously reported (17), and it reduced DGAT2 mRNA expression by about 60% in the WAT of Irs2 Ϫ/Ϫ mice whereas it significantly increased DGAT1 expression (Fig. 6, a-c).…”

Section: Intracerebroventricular Infusion Of Leptin Reduced Dgat2supporting

confidence: 54%

“…We previously reported that increased expression of sterol regulatory element binding protein-1 (SREBP-1) mRNA in the liver of Irs2 Ϫ/Ϫ mice causes fatty liver, and we attributed its development to leptin resistance (16). We have also reported that the obese phenotype in Irs2 Ϫ/Ϫ mice contributes to their insulin resistance (17).In this study, we discovered that the adipocytes of Irs2mice are hypertrophic and concluded that fatty acid and triglyceride synthesis must be activated in Irs2 Ϫ/Ϫ mouse adipocytes. Screening for genes involved in the fatty acid and triglyceride synthesis pathways revealed that DGAT2 mRNA was significantly up-regulated in Irs2 Ϫ/Ϫ mouse white adipose tissue (WAT) but that expression of DGAT1 was reduced.…”

mentioning

confidence: 67%

Section: Recently Dgat2mentioning

confidence: 99%

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Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Suzuki

Tobe

Aoyama

et al. 2005

Journal of Biological Chemistry

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Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2 ؊/؊ mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2 ؊/؊ mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.We have hypothesized that the size of adipocytes is inversely correlated with insulin sensitivity; namely, that larger adipocytes are associated with insulin resistance and smaller adipocytes are associated with insulin sensitivity (1). Acyl-CoA:diacylglycerol acyltransferase (DGAT) 1 is a key enzyme that catalyzes the final step in mammalian triglyceride synthesis (2), and two DGAT enzymes have been identified (3-5). Although the genes encoding DGAT1 and DGAT2 belong to different gene families, both genes are ubiquitously expressed and the enzymes they encode have similar substrate specificity (5). Dgat1 Ϫ/Ϫ mice have been reported to exhibit normal growth on a chow diet, and to be resistant to diet-induced obesity (6). Interestingly, Dgat1Ϫ/Ϫ mice exhibit increased insulin sensitivity and a leptin-sensitive phenotype associated with decreased tissue triglyceride content, suggesting that DGAT1 is somehow involved in insulin and leptin action throughout the body (7, 8). Recently, Dgat2Ϫ/Ϫ mice have been reported to exhibit marked reduction of triglyceride and fatty acids in the body, suggesting a critical role of DGAT2 in lipogenesis; however, the physiological roles of DGAT2 in adult mice are still unknown because Dgat2 Ϫ/Ϫ mice die soon after birth (9). The insulin receptor substrate (IRS) proteins play a key role in signal transduction from the insulin receptor (10, 11) and are major intracellular phosphorylation targets of activated insulin receptor tyrosine kinase. Irs2 Ϫ/Ϫ mice develop diabetes because of inadequate ␤-cell proliferation combined with insulin resistance (12-14). Another n...

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Section: Intracerebroventricular Infusion Of Leptin Reduced Dgat2supporting

confidence: 54%

mentioning

confidence: 67%

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Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Suzuki

Tobe

Aoyama

et al. 2005

Journal of Biological Chemistry

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“…There are several related IRS family members, including IRS-2, IRS-3, IRS-4, Gab-10, and p62 dok . IRS-2 has overlapping signaling potential, but does not restore insulin sensitivity in IRS-1 knockout mice (Suzuki et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate (IRS)‐1 regulates murine embryonic stem (mES) cells self‐renewal

Rubin

Arzumanyan

Soliera

et al. 2007

Journal Cellular Physiology

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Mouse embryonic stem (mES) cells are pluripotent cells that can be propagated in vitro with leukemia inhibitory factor (LIF) and serum. Intracellular signaling by LIF is principally mediated by activation of STAT-3, although additional pathways for self-renewal have been described. Here, we identified a novel role for Insulin receptor substrate-1 (IRS-1) as a critical factor in mES cells self-renewal and differentiation. IRS-1 is expressed and tyrosyl phosphorylated during mES cells self-renewal. Differentiation of mES cells, by LIF withdrawal, is associated with a marked reduction in IRS-1 expression. Targeting of IRS-1 by si-IRS-1 results in a severe reduction of Oct-4 protein expression and alkaline phosphatase activity, markers of undifferentiated mES cells. IRS-1 targeting does not interfere with LIF-induced STAT-3 phosphorylation, but negatively affects protein kinase B (PKB/AKT) and glycogen synthase kinase-3 (GSK-3b) phosphorylation, which are downstream effectors of the LIF-mediated PI3K signaling cascade. Targeting of IRS-1 also results in a marked down regulation of Id-1 and Id-2 proteins expression, which are important components for self-renewal of ES cells. Conversely, over expression of IRS-1 inhibits mES cell differentiation. Taken together, these results suggest that expression and activity of IRS-1 are critical to the maintenance of the self-renewal program in mES cells.

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“…Irs proteins lie downstream of the Insr and Igf-1r. Female Irs2 knockout mice showed infertile, hyperphagic, leptin resistant and developed obesity [100,101]. Mice lacking Irs2 in both pancreatic bcell and hypothalamic neuronal population using a rat insulin 2 promoter Cre (RIPCre) recombinase or in all neuron using Nestin promoter Cre (NesCre) demonstrated hypothalamic dysfunction [102][103][104].…”

Section: Hypothalamusmentioning

confidence: 99%

The FoxO transcription factors and metabolic regulation

2007

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Forkhead transcription factors FoxOs are conserved beyond species and regulated by insulin signaling pathway. FoxOs have diverse functions on differentiation, proliferation and cell survival. In calorie restriction (CR) or starvation, FoxOs are in nucleus, active transcriptionally, and increase hepatic glucose production, decrease insulin secretion, increase food intake and cause degradation of skeletal muscle for supplying substrates for glucose production. However, even in insulin resistance due to excessive calorie intake, FoxOs are active and causes type 2 diabetes and hyperlipidemia. The understanding of molecular mechanism how FoxOs affect glucose or lipid metabolism will shed light on the novel therapy of type 2 diabetes and the metabolic syndrome.

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Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2–/– Mice

Cited by 59 publications

References 61 publications

Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Insulin receptor substrate (IRS)‐1 regulates murine embryonic stem (mES) cells self‐renewal

The FoxO transcription factors and metabolic regulation

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