Ectopic fat accumulation in human astrocytes impairs insulin action

Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.

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Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis

International Journal of Molecular Sciences ◽

10.3390/ijms19123904 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3904 ◽

Cited By ~ 9

Author(s):

Jinhui Li ◽

Xiantao Wang ◽

William Ackerman ◽

Abel Batty ◽

Sean Kirk ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gene Expression Profile ◽

Expression Profile ◽

Underlying Mechanism ◽

Mitogen Activated Protein Kinase ◽

Acid Uptake ◽

Gram Negative ◽

E Coli

Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gram-negative sepsis by deactivating p38 and c-Jun N-terminal kinase (JNK). We have previously shown that Mkp-1+/+ mice, but not Mkp-1−/− mice, exhibit hypertriglyceridemia during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1−/− mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined the global gene expression profile in the livers via RNA-seq. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1−/− mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in the gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1−/− mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in downregulation of genes that facilitate fatty acid synthesis but upregulation of Cd36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a substantial change in triglyceride metabolic gene expression programs and Mkp-1 plays an important role in this process.

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Microarray Analysis of the Gene Expression Profile and Lipid Metabolism in Fat-1 Transgenic Cattle

PLoS ONE ◽

10.1371/journal.pone.0138874 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0138874 ◽

Cited By ~ 6

Author(s):

Xinfeng Liu ◽

Chunling Bai ◽

Xiangbin Ding ◽

Zhuying Wei ◽

Hong Guo ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Gene Expression Profile ◽

Microarray Analysis ◽

Expression Profile ◽

Transgenic Cattle

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Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e859 ◽

1997 ◽

Vol 273 (5) ◽

pp. E859-E867 ◽

Cited By ~ 4

Author(s):

M. Hettiarachchi ◽

S. Chalkley ◽

S. M. Furler ◽

Y.-S. Choong ◽

M. Heller ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Insulin Action ◽

Glycogen Synthesis ◽

Human Growth ◽

Whole Body ◽

Nonesterified Fatty Acids ◽

Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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Early Hepatic Gene Expression Profile of Lipid Metabolism of Mice on High Fat Diet after Treatment with Anti‐Obesity Drugs

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.03810 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Nasser M. Rizk ◽

Amina Saleh ◽

Dina Elsayegh ◽

Abdelrahman Algamal

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Gene Expression Profile ◽

Expression Profile ◽

High Fat Diet ◽

Hepatic Gene Expression ◽

High Fat ◽

Obesity Drugs

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Hepatic Gene Expression Profile of Lipid Metabolism in Rats: Impact of Caloric Restriction and Growth Hormone/Insulin-Like Growth Factor-1 Suppression

The Journals of Gerontology Series A ◽

10.1093/gerona/61.11.1099 ◽

2006 ◽

Vol 61 (11) ◽

pp. 1099-1110 ◽

Cited By ~ 19

Author(s):

Y. Higami ◽

T. Tsuchiya ◽

T. Chiba ◽

H. Yamaza ◽

I. Muraoka ◽

...

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Lipid Metabolism ◽

Growth Factor ◽

Caloric Restriction ◽

Gene Expression Profile ◽

Expression Profile ◽

Hepatic Gene Expression ◽

Insulin Like Growth Factor

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Zinc-α2-Glycoprotein Knockout Influenced Genes Expression Profile in Adipose Tissue and Decreased the Lipid Mobilizing After Dexamethasone Treatment in Mice

Hormone and Metabolic Research ◽

10.1055/a-1186-0649 ◽

2020 ◽

Vol 52 (10) ◽

pp. 755-763

Author(s):

Wenge Zhang ◽

Yu Qiao ◽

Fulei Qi ◽

Qingyi Shen ◽

Ruqian Zhao ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gene Expression Profile ◽

Expression Profile ◽

Visceral Fat ◽

Fatty Acid Synthase ◽

Wild Type ◽

Genes Expression

AbstractZinc-α2-glycoprotein (ZAG), as an adipokine, plays an important role in lipid metabolism. However, its influence on whole gene expression profile in adipose tissue is not known. Under stress condition, how ZAG affects the lipid metabolism is also unclear. Therefore, in this study ZAG systemic knockout (KO) mice were used as a model to reveal the genes expression profile in visceral fat tissues of ZAG KO mice and wild-type mice by genome-wide microarray screening. Then dexamethasone (DEX) was used to explore the effect of ZAG deletion on body fat metabolism under stress. Our results showed that 179 genes were differentially expressed more than 1.5 times between ZAG KO mice and wild type mice, of which 26 genes were upregulated dramatically and 153 genes were significantly downregulated. Under DEX simulated stress, ZAG systemic knockout in vivo resulted in a markedly decrease of triglycerides (TG) and nonesterified fatty acid (NEFA) content in in plasma. Similarly, for lipid catabolism, ZAG KO led to a significant increase of phosphorylated HSL (p-HSL) protein and a rising tendency of adipose triglyceride lipase (ATGL) protein relative to those of the DEX group. For lipid anabolism, fatty acid synthase (FAS) and adiponectin protein expression in visceral fat rose notably in ZAG KO mice after DEX treatment. In conclusion, ZAG knockout can affect the gene expression profile of adipose tissue, reduce elevated TG and NEFA levels in plasma, and alter lipid metabolism under DEX treatment. These findings provide new insights into the mechanism of lipid metabolic disorders in response to stress.

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