Altered metabolic gene expression in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes

Nie, Tina; Zhang, Shaoping; Amarsingh, Greeshma Vazhoor; Liu, Hong; McCann, Mark J.; Cooper, Garth J. S.

doi:10.1038/s41598-019-51088-x

Cited by 5 publications

(4 citation statements)

References 63 publications

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“…Amylin is a β-cell hormone involved in the slowing of gastric emptying ( Young, 2005 ), inhibition of insulin secretion ( Silvestre et al, 1990 ), antagonizing insulin action in skeletal muscle ( Leighton and Cooper, 1988 ), and suppression of appetite via modulation of neuropeptide signaling ( Nie et al, 2019 ).…”

Section: The Role Of Amylin In the Pathogenesis Of β-Cell Dysfunction And T2dmmentioning

confidence: 99%

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Nie

Cooper

2021

Front. Pharmacol.

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Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.

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Section: The Role Of Amylin In the Pathogenesis Of β-Cell Dysfunction And T2dmmentioning

confidence: 99%

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Nie

Cooper

2021

Front. Pharmacol.

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“…Glucose has been established as a regulator of gene expression in several tissues, but glucose-dependent gene expression in hypothalamic cells has not yet been analyzed in detail [ 36 , 54 , 55 , 56 , 57 ]. Altered gene expression has been reported in the brain of diabetic rodents, but in vivo models can hardly differentiate between the effects of glucose or insulin on gene expression [ 58 , 59 ]. Herein, we analyzed glucose-dependent gene expression in vitro, independent of insulin using a hypothalamic cell line and a four-step strategy: (1) we determined the entire transcriptome of cells at low and high glucose levels by RNA-seq; (2) we selected candidates and re-evaluated their glucose-dependent mRNA levels by qRT-PCR; (3) we monitored protein expression levels by ELISA; and (4) we determined cholesterol levels, second messengers, or reporter gene activities at different glucose concentrations.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells

Webert¹,

Faro²,

Zeitlmayr³

et al. 2022

Cells

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Glucose provides vital energy for cells and contributes to gene expression. The hypothalamus is key for metabolic homeostasis, but effects of glucose on hypothalamic gene expression have not yet been investigated in detail. Thus, herein, we monitored the glucose-dependent transcriptome in murine hypothalamic mHypoA-2/10 cells by total RNA-seq analysis. A total of 831 genes were up- and 1390 genes were downregulated by at least 50%. Key genes involved in the cholesterol biosynthesis pathway were upregulated, and total cellular cholesterol levels were significantly increased by glucose. Analysis of single genes involved in fundamental cellular signaling processes also suggested a significant impact of glucose. Thus, we chose ≈100 genes involved in signaling and validated the effects of glucose on mRNA levels by qRT-PCR. We identified Gnai1–3, Adyc6, Irs1, Igfr1, Hras, and Elk3 as new glucose-dependent genes. In line with this, cAMP measurements revealed enhanced noradrenalin-induced cAMP levels, and reporter gene assays elevated activity of the insulin-like growth factor at higher glucose levels. Key data of our studies were confirmed in a second hypothalamic cell line. Thus, our findings link extra cellular glucose levels with hypothalamic lipid synthesis and pivotal intracellular signaling processes, which might be of particular interest in situations of continuously increased glucose levels.

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“…Glucose has been established as a regulator of gene expression in several tissues, but glucose-dependent gene expression in hypothalamic cells has not yet been analysed in detail 36,[48][49][50][51] . Altered gene expression has been reported in the brain of diabetic rodents, but in vivo models can hardly differentiate between the effects of glucose or insulin on gene expression 52,53 . Herein, we analysed glucose-dependent gene expression in vitro, independent of insulin using a hypothalamic cell line and a four-step strategy: 1) We determined the entire transcriptome of cells at low and high glucose levels by RNA-seq.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells

Webert

Faro

Zeitlmayr

et al. 2021

Preprint

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We have previously shown that glucose activates CREB-regulated transcriptional co-activator-2 (CRTC-2) in murine, hypothalamic (mHypoA-2/10) cells. Thus, we now analysed the entire glucose-dependent transcriptome of mHypoA-2/10 cells by total RNA-seq. 831 genes were up- and 1390 genes down-regulated by at least 50 %. Signalling pathway analysis revealed activation of the cholesterol biosynthesis pathway by glucose. Accordingly, protein expression of both sterol regulatory element-binding proteins (SREBP) and total cholesterol levels were enhanced by glucose. Analysis of single genes involved in fundamental signalling processes suggested a significant impact of glucose. Thus, we chose ~100 genes and validated the effects of glucose on mRNA levels by qRT-PCR. We identified 15 genes with strong glucose-dependent mRNA expression. Among these genes were gnai1 to -3, adyc6, irs1, igfr1, hras and elk3. cAMP measurements revealed decreased basal and enhanced noradrenalin-induced cAMP levels at higher glucose concentrations. Serum-response element-dependent reporter assays indicated enhanced basal and insulin-like growth factor-induced activity at higher glucose levels. siRNA against CRTC-2 dampened the effects of glucose on cholesterol synthesis and IRS-1, SREBP-1, SREBP-2 or AC-6 protein expression. These findings could help to understand the functional consequences of physiologically occurring alterations of extracellular glucose concentrations as well as pathologically increased glucose levels.

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Altered metabolic gene expression in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes

Cited by 5 publications

References 63 publications

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Mechanisms Underlying the Antidiabetic Activities of Polyphenolic Compounds: A Review

Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells

Analysis of the Glucose-Dependent Transcriptome in Murine Hypothalamic Cells

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