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A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling.

ABSTRACT: A transcript of unknown function, regulated by fasting and feeding, was identified by microarray analysis. The transcript is up-regulated in the fasting state. An 1168-bp cDNA was cloned from rat hypothalamus and sequenced. This sequence is consistent with adipogenesis down-regulating transcript 3 (AGD3) (also known as human OCC-1) mRNA. A protein sequence identical to AGD3 was determined by mass spectrometry. In the rat brain, AGD3 mRNA is distributed in the arcuate nucleus, ventromedial hypothalamus, amygdaloid nuclei, hippocampus, and somatic cortex. Double in situ hybridisation showed that AGD3 mRNA is co-localised with pro-opiomelanocortin and neuropeptide Y in arcuate nucleus neurones. AGD3 binds with insulin receptor substrate 4 and increases insulin-stimulated phospho-Akt and regulates AMP-activated protein kinase and mammalian target of rapamycin downstream target S6 kinase phosphorylation.

SUBMITTER: Chai B

PROVIDER: S-EPMC4651207 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling.

Chai B B Li J-Y JY Fritze D D Zhang W W Xia Z Z Mulholland M W MW

Journal of neuroendocrinology 20130301 3

A transcript of unknown function, regulated by fasting and feeding, was identified by microarray analysis. The transcript is up-regulated in the fasting state. An 1168-bp cDNA was cloned from rat hypothalamus and sequenced. This sequence is consistent with adipogenesis down-regulating transcript 3 (AGD3) (also known as human OCC-1) mRNA. A protein sequence identical to AGD3 was determined by mass spectrometry. In the rat brain, AGD3 mRNA is distributed in the arcuate nucleus, ventromedial hypoth ...[more]

PMID: 22935015

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Project description:Seasonal animals adapt their physiology and behaviour in anticipation of climate change to optimise survival of their offspring. Intra-hypothalamic thyroid hormone signalling plays an important role in seasonal responses in mammals and birds. In the F344 rat, photoperiod stimulates profound changes in food intake, body weight and reproductive status. Previous investigations of the F344 rat have suggested a role for thyroid hormone metabolism, but have only considered Dio2 expression, which was elevated in long day photoperiods. Microarray analysis was used to identify time-dependent changes in photoperiod responsive genes, which may underlie the photoperiod-dependent phenotypes of the juvenile F344 rat. The most significant changes are those related to thyroid hormone metabolism and transport. Using photoperiod manipulations and melatonin injections into long day photoperiod (LD) rats to mimic short day (SD), we show photoinduction and photosuppression gene expression profiles and melatonin responsiveness of genes by in situ hybridization; TSHβ, CGA, Dio2 and Oatp1c1 genes were all elevated in LD whilst in SD, Dio3 and MCT-8 mRNA were increased. NPY was elevated in SD whilst GALP increased in LD. The photoinduction and photosuppression profiles for GALP were compared to that of GHRH with GALP expression following GHRH temporally. We also reveal gene sets involved in photoperiodic responses, including retinoic acid and Wnt/ß-catenin signalling. This study extends our knowledge of hypothalamic regulation by photoperiod, by revealing large temporal changes in expression of thyroid hormone signalling genes following photoperiod switch. Surprisingly, large changes in hypothalamic thyroid hormone levels or TRH expression were not detected. Expression of NPY and GALP, two genes known to regulate GHRH, were also changed by photoperiod. Whether these genes could provide links between thyroid hormone signalling and the regulation of the growth axis remains to be investigated.

Project description:PurposeInsulin receptor (InsR) sensitizers represent a new type of therapeutic agent for the treatment of diabetes, with 2'-O-methylperlatolic acid (2-O-M) being a potential InsR targeting drug. The purpose of this study was to determine whether 2-O-M functions as an activator of the insulin signaling pathway, regulating glucose hemostasis through the InsR and exerting a glucose-lowering effect in an animal model of diabetes.MethodsSPR-based analyses were used to detect the binding of different concentrations of 2-O-M to the InsR. The protein levels of IR-β, p-IR, AKT, and p-AKT in Hepa and C2C12 cell lines and liver and muscle tissues were determined by western blotting. Glucose uptake capacity was determined in C2C12 cells. Streptozotocin-induced diabetic mice were randomly divided into four groups: the control, insulin treated, 2-O-M treated, and combined insulin and 2-O-M treated. Mice were injected with 2-O-M or normal saline and the average blood glucose concentration after 120 min, and the serum levels of insulin, glucagon, and C-peptide were measured. Next, qRT-PCR was performed to detect the mRNA expression of genes involved in lipid and glucose metabolism in the liver and muscle tissues.Results2-O-M binds to the extracellular domain of the InsR. Moreover, combination treatment with 2-O-M and insulin resulted in significant activation of the insulin signaling pathway in vitro and significant stimulation of the glucose uptake capacity of C2C12 myotubes. In mice with streptozotocin-induced diabetes, 2-O-M significantly prolonged the blood glucose-lowering effect of insulin, significantly reduced the secretion of exogenous insulin, and reduced the blood glucose concentration in vivo. In addition, treatment with 2-O-M alone significantly enhanced the phosphorylation of AKT in muscle tissue, which enhanced glucose uptake in C2C12 myotubes. Further, 2-O-M significantly increased glucagon secretion and enhanced liver gluconeogenesis to prevent hypoglycemia.Conclusion2-O-M enhances the hypoglycemic effect of insulin through the insulin signaling pathway and can be used as a complement to insulin. This synergetic effect may lower the required dose of insulin and protect β cells.

Dataset Information

A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling.

Publications

A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling.

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