Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.

Anai, Motonobu; Funaki, Makoto; Ogihara, Takehide; Kanda, Akira; Onishi, Yukiko; Sakoda, Hideyuki; Inukai, Kouichi; Nawano, Masao; Fukushima, Yasushi; Yazaki, Yoshio; Kikuchi, Masatoshi; Oka, Yoshitomo; Asano, Tomohiko

doi:10.2337/diabetes.48.1.158

Cited by 88 publications

(64 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The impaired SKM insulin signaling is crucial for systemic insulin resistance and precedes the development of diabetes (DeFronzo & Tripathy 2009, Pagel-Langenickel et al 2010. However, our study showed that HFD exerts minor effects on Irs1 and Glut4 mRNA in SKM compared with the change in WAT, agreeing with a previous report (Anai et al 1999). NEFA uptake by SKM is controlled by both circulating lipid levels and specific transporters, particularly LPL and FAT/CD36 (Koonen et al 2005, Goldberg et al 2009).…”

Section: Discussionsupporting

confidence: 80%

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

Liu¹,

Lim²,

Su³

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

Neonatal overnutrition results in accelerated development of high-fat diet (HFD)-induced metabolic defects in adulthood. To understand whether the increased susceptibility was associated with aggravated inflammation and dysregulated lipid metabolism, we studied metabolic changes and insulin signaling in a chronic postnatal overnutrition (CPO) mouse model. Male Swiss Webster pups were raised with either three pups per litter to induce CPO or ten pups per litter as control (CTR) and weaned to either low-fat diet (LFD) or HFD. All animals were killed on the postnatal day 150 (P150) except for a subset of mice killed on P15 for the measurement of stomach weight and milk composition. CPO mice exhibited accelerated body weight gain and increased body fat mass prior to weaning and the difference persisted into adulthood under conditions of both LFD and HFD. As adults, insulin signaling was more severely impaired in epididymal white adipose tissue (WAT) from HFD-fed CPO (CPO-HFD) mice. In addition, HFD-induced upregulation of pro-inflammatory cytokines was exaggerated in CPO-HFD mice. Consistent with greater inflammation, CPO-HFD mice showed more severe macrophage infiltration than HFD-fed CTR (CTR-HFD) mice. Furthermore, when compared with CTR-HFD mice, CPO-HFD mice exhibited reduced levels of several lipogenic enzymes in WAT and excess intramyocellular lipid accumulation. These data indicate that neonatal overnutrition accelerates the development of insulin resistance and exacerbates HFD-induced metabolic defects, possibly by worsening HFD-induced inflammatory response and impaired lipid metabolism.

show abstract

Section: Discussionsupporting

confidence: 80%

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

Liu¹,

Lim²,

Su³

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Acute intravenous infusion of leptin (46) and high fat feeding (47), which increase leptin levels, have been shown to increase IRS-1-associated PI 3-kinase in liver in vivo, whereas leptin treatment of C 2 C 12 cells in vitro increases IRS-2-associated PI 3-kinase (12). In Fao cells, the leptin-induced alterations in the insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 resulted in corresponding and divergent changes in the association of the p85 subunit of the PI 3-kinase with these substrates.…”

Section: Discussionmentioning

confidence: 99%

Selective interaction between leptin and insulin signaling pathways in a hepatic cell line

Szántó

Kahn

2000

Proc. Natl. Acad. Sci. U.S.A.

175

139

View full text Add to dashboard Cite

Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulininduced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.T he product of the ob gene is leptin, a 16-kDa peptide hormone produced by adipocytes that acts in the hypothalamus and plays a central role in regulation of feeding behavior and energy homeostasis (1-4). The leptin receptor (OB-R) occurs in several isoforms that differ in the length of their intracellular domains because of alternative splicing of the gene (5, 6). The long form is termed OB-Rb or OB-R L and is expressed abundantly in specific nuclei of the hypothalamus. The short forms, OB-Ra, c, d, and e (collectively referred to OB-R S ), have a wide tissue distribution. The long form of the OB-R belongs to the gp130 family of cytokine receptors that also includes the receptor for IL-6, leukocyte inhibitory factor, and granulocyte colony stimulating factor. These receptors act by activating cytoplasmic tyrosine kinases of the Janus kinase (JAK) family that in return phosphorylate specific transcription factors of the Stat (signal transducer and activator of transcription) family (7-10). On phosphorylation, the Stat proteins dimerize and translocate to the nucleus where they bind to specific nucleotide sequences and induce gene expression. Despite the abundance of the short forms of receptor, little is known about their physiological significance. Cells transfected with the short form of receptor may be capable of activating JAK kinases but fail to phosphorylate Stat proteins or activate gene expression (6,8).In vivo and in vitro evidence supports the hypothesis that leptin and insulin signaling networks may be connected at s...

show abstract

“…Impaired insulin-stimulated translocation of GLUT4 to the plasma membrane has been shown in the insulin-resistant obese Zucker rat (13) and in incubated muscle strips from type 2 diabetic subjects (14). In muscles and adipose tissue biopsies from high-fat-fed rats (15) and also in muscles from obese subjects (16), impaired activation of PI 3-kinase has been observed. In a recently published study that investigated the effect of high-fat feeding in normal rats, it was demonstrated that an insulin-mediated but not a contraction-activated pathway for glucose transport was impaired due to reduced translocation of GLUT4.…”

mentioning

confidence: 96%

Muscle glucose uptake is effectively activated by ischemia in type 2 diabetic subjects.

et al. 2000

View full text Add to dashboard Cite

It has previously been shown that Wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibits glucose transport activated by insulin but not by ischemia, suggesting the importance of an activating mechanism that bypasses the insulin signal. To evaluate the relevance of this insulin-independent pathway in insulin-resistant subjects, the ability of ischemia to stimulate glucose uptake was investigated in 9 patients with type 2 diabetes and in 9 healthy control subjects (fasting glucose level 9.4 ± 0.8 vs. 5.1 ± 0.1 mmol/l, P < 0.001, in type 2 diabetic patients and control subjects, respectively; fasting insulin level insulin 8.1 ± 2.6 vs. 4.5 ± 0.7 mU/l, P < 0.05, respectively) matched for sex, age, and BMI. Arterial plasma and interstitial concentrations of glucose and lactate (measured by subcutaneous and muscle microdialysis) were recorded in the forearm before, during, and after ischemia induced locally for 20 min. During ischemia, the muscle interstitial glucose concentration decreased significantly from 7.7 ± 0.6 to 5.4 ± 0.4 mmol/l (P < 0.01) and from 4.4 ± 0.3 to 3.6 ± 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. The arterial-interstitial (A-I) glucose concentration difference was 1.7 ± 0.6 and 0.7 ± 0.3 mmol/l at basal, and it increased significantly to 3.5 ± 0.7 (P < 0.01) and 1.4 ± 0.3 mmol/l (P < 0.05) during ischemia in each group, respectively. Interstitial lactate increased significantly during ischemia from 0.8 ± 0.1 to 1.1 ± 0.1 mmol/l (P < 0.05) and from 0.5 ± 0.1 to 0.9 ± 0.2 mmol/l (P < 0.05), respectively. The A-I glucose concentration difference was abolished immediately postischemia and regained after ~15 min, whereas high interstitial lactate levels remained elevated throughout the study. Subcutaneous interstitial glucose concentrations remained unchanged during ischemia and postischemia in both groups, whereas the interstitial lactate concentration in adipose tissue increased during ischemia from 1.4 ± 0.2 to 2.0 ± 0.2 mmol/l (P < 0.05) and from 1.1 ± 0.1 to 1.8 ± 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. Plasma glucose and lactate levels were unchanged in both groups during the study period. The results show that in muscle, but not in adipose tissue, glucose uptake is efficiently activated by ischemia in insulin-resistant type 2 diabetic subjects, suggesting the activation of a putative alternative pathway to the insulin signal in muscle cells. Diabetes 49:1178-1185, 2000 I n skeletal muscle, insulin activates glucose transport through the translocation of GLUT4 from intracellular compartments to the plasma membrane (1). At least 2 distinct signaling pathways for the activation of glucose transport have been detected. In addition to the pathway used by the insulin signal, another pathway activated by contraction or ischemia has been described (2,3). One argument for multiple independent pathways for activation of glucose transport has been based on the observation that a maximal stimulation of glucos...

show abstract

Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats.

Cited by 88 publications

References 29 publications

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

Selective interaction between leptin and insulin signaling pathways in a hepatic cell line

Muscle glucose uptake is effectively activated by ischemia in type 2 diabetic subjects.

Contact Info

Product

Resources

About