Whole body deficiency of G6P is characterized by hypoglycemia, hyperlipidemia and hepatic disorder 28 , However, mice with liver-specific deletion of G6P exhibit normoglycemia in the fed state Thus, it seems questionable that G6pc alone in the liver is sufficient to lower glucose levels.
Improvement of insulin sensitivity in Notch1-deficient mice could be the combined result of G6P and other effects on metabolism. In agreement with this hypothesis, previous studies have shown that Notch1 signaling can regulate the hepatic lipogenic program through actions on lipogenic gene expression Our current data reveal a previously unknown role for Notch1 signaling in the regulation of oxidative genes. Reduced levels of G6P and increased expression of lipid oxidation genes may explain the increased insulin sensitivity observed in Notch1-deficient mice.
The present study employed mice ubiquitously expressing Notch1 antisense driven by the mouse mammary tumor virus long terminal repeat promoter. These mice were more insulin sensitive under high-fat diet-fed obese conditions compared with the wild type control mice.
Similar to the effects in hepatocytes, the expression levels of oxidative genes in adipocytes were also increased. However, body weight gain and food intake upon HFD feeding were not different in NAS mice compared with control mice, suggesting that enhanced insulin sensitivity in the NAS mice may be attributed to the actions of increased expression of hepatic oxidative genes.
At present, the reason for the differential impacts of Notch1 signaling on lipid accumulation in adipose tissue and liver are unclear. This may be due to the redundant effect of other Notch1 family members in adipose tissues.
Indeed, Notch1, 2, 3 and 4 are also expressed in fat tissues, suggesting potential redundant effects of Notch family members in fat tissues. Alternatively, liver-specific or adipose tissue-specific Notch1-deleted mice may exhibit tissue-specific metabolic effects on Notch1 signaling due to pleiotropic effects of Notch1 signaling in various tissues.
Indeed, adipose-specific inactivation of Notch1 reduced fat mass and improved insulin sensitivity, corroborating the conserved roles of Notch1 signaling in adipose tissues Thus, it is reasonable to suggest that Notch1 may play a conserved role in hepatocytes and adipocytes. However, liver-specific Notch1-deleted mice will be required to definitively show hepatocyte-specific effects of Notch1 signaling in fatty liver, as well as metabolic effects, in the future.
It remains to be determined how Notch1 signaling regulates the expression of these oxidative genes. One possibility is that Hes1 may function as an inhibitory mediator of Notch signaling. Previous studies have shown that Hes1, a direct target of Notch signaling, behaved as a transcriptional repressor through its binding to the E-Box region on target promoters Alternatively, NICD1 itself may regulate the expression of lipid oxidation genes indirectly by modulating transcriptional activators or repressors that in turn affect the expression of oxidative genes.
Determining whether there are direct effects of Hes1 and NICD on promoters of genes that encode lipid oxidation proteins is an intriguing avenue that should be explored in the future. In the present study, we identified Notch1 signaling as a key determinant of triacylglycerol metabolism in response to a high fat diet and we further revealed novel biological actions of Notch1 signaling pathways on the regulation of lipid oxidation.
All animal studies were carried out in accordance with and with approval from, the Animal Research Committee of Sungkyunkwan University. Notch1 antisense transgenic NAS mice were generated as described previously These mice were individually housed and allowed free access to water and food Solid feed 5L79, Orient.
LTD, Seoul, Korea. After an adaptation period of 1 week, 9-week-old mice were randomly assigned into four groups. Body weight was measured twice per week and food intake was determined three times per week. For insulin tolerance tests, random fed-mice were injected i.
Louis, MO , 0. Every 2 days, cells were refreshed with media containing FBS and insulin. ORO stained cells from at least two independent experiments were quantified by extracting dye with isopropanol. Retroviral or lentivrial overexpression of NICD was performed using pBabe-puro and the packaging cell line of the Phoenix system as described previously Louis, MO. Isolated RNA was further cleaned by phenol-chloroform extraction, followed by ethanol precipitation.
Expression was normalized to 36B4. All real-time PCRs were performed at least twice. Seoul, Korea. To assess the effects on lipid accumulation, the transfected cells were induced and differentiated into adipocytes for 7 days followed by ORO staining or total RNA extraction for real-time PCR. Transfections were carried out in triplicates. HepG2 cells were seeded in well plates at a density of 2.
The medium was removed to a sealed container and the l4 CO 2 was extracted by mixing with 0. The amount of 14 CO 2 was measured using a liquid scintillation counter. The total protein concentrations of cells were determined for normalization.
Statistical significance was considered when a p value was less than 0. How to cite this article : Song, N. Notch1 deficiency decreases hepatic lipid accumulation by induction of fatty acid oxidation. Kahn, B. Obesity and insulin resistance. The Journal of clinical investigation , — Wang, Y. Lancet , — Article Google Scholar. Kopelman, P. Obesity as a medical problem. Nature , — Waki, H. Endocrine functions of adipose tissue.
Annual review of pathology 2, 31—56 Tontonoz, P. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77, — Hong, J. Further understanding of fat biology: lessons from a fat fly.
Exp Mol Med 42, 12—20 Rosen, E. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4, — Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7, — Perdigoto, C. Sending the right signal: Notch and stem cells. Biochim Biophys Acta , — Selkoe, D. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26, — Park, J.
Inhibition of Notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis Arumugam, T. Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nature medicine 12, — Fortini, M. Notch signaling: the core pathway and its posttranslational regulation.
Dev Cell 16, — Pajvani, U. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nature medicine 17, — Fowler, J. Related: Want an Apple laptop? Here are the best you can buy right now. The MacBook Pro design has been ripped off to death by a lot of other laptop manufacturers over the years.
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Apple also mentions in the support document that this scaling feature will disappear once developers update their apps to deal with the notch correctly. Subscribe to get the best Verge-approved tech deals of the week. Cookie banner We use cookies and other tracking technologies to improve your browsing experience on our site, show personalized content and targeted ads, analyze site traffic, and understand where our audiences come from.
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