Role of fatty acid elongase Elovl6 in the sucrose preference formation

科学研究費助成事業(学術研究助成基金助成金)研究成果報告書：挑戦的萌芽研究2012-2012課題番号：2465944

CREBH Regulates Systemic Glucose and Lipid Metabolism

The cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH, encoded by CREB3L3) is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL) activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα), has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα) in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine

Elovl6による脂肪酸の質的変容が起こす多臓器代謝病態と脳行動異常のメカニズム

科学研究費助成事業 研究成果報告書：基盤研究(A)2015-2017課題番号 : 15H0254

Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes

AbstractSterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor which regulates genes involved in the synthesis of fatty acids and triglycerides. The overexpression of nuclear SREBP-1a in transgenic mice under the control of the PEPCK promoter (TgSREBP-1a) caused a massively enlarged fatty liver and disappearance of peripheral white adipose tissue. In the current study, we estimated the impact of this lipid transcription factor on plasma glucose/insulin metabolism in vivo. TgSREBP-1a exhibited mild peripheral insulin resistance as evidenced by hyperinsulinemia both at fasting and after intravenous glucose loading, and retarded glucose reduction after insulin injection due to decreased plasma leptin levels. Intriguingly, hyperinsulinemia in TgSREBP-1a mice was markedly exacerbated in a fed state and sustained after intravenous glucose loading, and paradoxically decreased after the portal injection of glucose. TgSREBP-1a mice consistently showed very small plasma glucose increases after portal glucose loading because of a large capacity for hepatic glucose uptake. These data suggested that hepatic insulin resistance emerges postprandially. In addition, pancreatic islets from TgSREBP-1a were enlarged. These data demonstrate that SREBP-1a activation in the liver has a strong impact on plasma insulin levels, implicating the potential role of SREBPs in hepatic insulin metabolism relating to insulin resistance

Mitochondrial intermediate peptidase is a novel regulator of sirtuin-3 activation by caloric restriction

Sirtuin-3 (SIRT3) regulates mitochondrial quality and is involved in the anti-ageing and pro-longevity actions of caloric restriction (CR). Here, we show that CR upregulates the mature form of SIRT3 and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in white adipose tissue. We also demonstrate that upregulation of mature SIRT3 is dependent on MIPEP in 3T3-L1 cells, suggesting that MIPEP may contribute to the maintenance of mitochondrial quality during CRvia activation of SIRT3. This novel mechanism of SIRT3 activation through MIPEP facilitates the elucidation of additional molecular pathways of CR

Development of a bioassay to screen for chemicals mimicking the anti-aging effects of calorie restriction

Suppression of the growth hormone/insulin-like growth factor-I pathway in Ames dwarf (DF) mice, and caloric restriction (CR) in normal mice extends lifespan and delays the onset of age-related disorders. In combination, these interventions have an additive effect on lifespan in Ames DF mice. Therefore, common signaling pathways regulated by DF and CR could have additive effects on longevity. In this study, we tried to identity the signaling mechanism and develop a system to assess pro-longevity status in cells and mice. We previously identified genes up-regulated in the liver of DF and CR mice by DNA microarray analysis. Motif analysis of the upstream sequences of those genes revealed four major consensus sequence motifs, which have been named dwarfism and calorie restriction-responsive elements (DFCR-REs). One of the synthesized sequences bound to hepatocyte nuclear factor-4α (HNF-4α), an important transcription factor involved in liver metabolism. Furthermore, using this sequence information, we developed a highly sensitive bioassay to identify chemicals mimicking the anti-aging effects of CR. When the reporter construct, containing an element upstream of a secreted alkaline phosphatase (SEAP) gene, was co-transfected with HNF-4α and its regulator peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α), SEAP activity was increased compared with untransfected controls. Moreover, transient transgenic mice established using this construct showed increased SEAP activity in CR mice compared with ad libitum-fed mice. These data suggest that because of its rapidity, ease of use, and specificity, our bioassay will be more useful than the systems currently employed to screen for CR mimetics, which mimic the beneficial effects of CR. Our system will be particularly useful for high-throughput screening of natural and synthetic candidate molecules

Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome

Obesity causes various health problems, such as type 2 diabetes, non-alcoholic fatty liver disease, and cardio- and cerebrovascular diseases. Metabolic organs, particularly white adipose tissue (WAT) and liver, are deeply involved in obesity. WAT contains many adipocytes with energy storage capacity and secretes adipokines depending on the obesity state, while liver plays pivotal roles in glucose and lipid metabolism. This review outlines and underscores the relationship between obesity and lysosomal functions, including lysosome biogenesis, maturation and activity of lysosomal proteases in WAT and liver. It has been revealed that obesity-induced abnormalities of lysosomal proteases contribute to inflammation and cellular senescence in adipocytes. Previous reports have demonstrated obesity-induced ectopic lipid accumulation in liver is associated with abnormality of lysosomal proteases as well as other lysosomal enzymes. These studies demonstrate that lysosomal dysfunction in WAT and liver underlies part of the obesity-related pathology, raising the possibility that strategies to modulate lysosomal function may be effective in preventing or treating the metabolic syndrome