E4orf1: A protein for enhancing glucose uptake despite impaired proximal insulin signaling

Shastri, Anuradha; Hegde, Vijay; Peddibhotla, Swetha; Feizy, Zahra; Dhurandhar, Nikhil V.

doi:10.1371/journal.pone.0208427

Cited by 14 publications

(8 citation statements)

References 39 publications

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“…Generally, in vivo reduction in insulin concomitant with an improvement in glycemic control is due to the improvement in insulin sensitivity. However, E4orf1 upregulates cellular glucose uptake independent of proximal insulin signaling 18,19 and does not improve insulin sensitivity [16][17][18] , yet it reduces endogenous insulin response 17 . The E4orf1-mediated reduction in insulin is not due to pancreatic beta cell damage or due to reduced ability of beta cells to secrete insulin 16,17 .…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that, in the mouse model of E4orf1 expression in adipose tissue, reduced levels of insulin, a lipogenic hormone, will be associated with reduced hepatic lipogenesis and steatosis. Another important aspect of the metabolic effects of E4orf1 is its potential as a drug to treat type 1 or type 2 diabetes [13][14][15][16]18,19 . While the effect of E4orf1 on HF-diet induced hyperglycemia is reported [13][14][15] , it is unclear whether E4orf1 will further reduce glucose levels in normoglycemic mice on a chow diet.…”

Section: Introductionmentioning

confidence: 99%

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Reducing endogenous insulin is linked with protection against hepatic steatosis in mice

et al. 2020

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Background: Obesity and type 2 diabetes (T2D) are closely associated with hepatic steatosis (HS), which if untreated can advance to serious liver conditions. Since insulin promotes hepatic lipogenesis, reducing hyperinsulinemia may help in treating HS. E4orf1 is an adenovirus-derived protein that improves glucose clearance independent of insulin, lowers insulin amount required for glucose disposal, and reduces HS. As a next step, we evaluated the mechanism for E4orf1-induced reduction in HS and tested that E4orf1 does not induce hypoglycemia, an important attribute for its application as a potential anti-diabetic agent.Methods: C57Bl/6J mice that transgenically express E4orf1 in adipose tissue (E4orf-Tg) and wild-type (WT) mice received a chow diet for 6 weeks, followed by a high-fat (HF) diet for additional 10 weeks. Body composition, blood glucose, and serum insulin levels upon glucose load were measured at 0, 6, 7, and 16 weeks. Serum free fatty acid (FFA), triglyceride (TG), and hepatic TG were measured at study termination. We compared histology and the mRNA/ protein markers of hepatic and adipose tissue lipid metabolism between the two groups of mice.Results: On chow diet, both groups remained normoglycemic, but E4orf1 expression reduced insulin response. On HF diet, glycemic control in WT deteriorated, whereas E4orf1 significantly enhanced glycemic control, lowered insulin response, reduced hepatic triglycerides, and serum FFA. Overall, a comparison of hepatic mRNA and/or protein expression suggested that E4orf1 expression significantly decreased de novo lipogenesis (DNL) and intracellular lipid transport and increased fat oxidation and TG export. Adipose tissue mRNA and protein markers suggested that E4orf1 expression lowered DNL and increased lipolysis. Conclusion:Considering that E4orf1 is not secreted in circulation, we postulate that reduced endogenous insulin in E4orf1 mice indirectly contributes to reduce HS by altering hepatic lipid metabolism, including lipogenesis. This study underscores the possibility of indirectly impacting HS by manipulating adipose tissue metabolism. Nutrition and Diabetes1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reducing endogenous insulin is linked with protection against hepatic steatosis in mice

et al. 2020

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“…Independent of the virus, E4orf1 protein promotes glucose uptake in adipocytes, myoblasts and reduces glucose output from hepatocytes 8,9,11–13,17 , and in vivo, it improves high fat induced hyperglycemia, and reduces the response of endogenous insulin to glucose load 14–16 . Most importantly, E4orf1 promotes cellular glucose disposal in the absence of insulin 9 or independent of the proximal insulin signaling 11,33 . This property is highly attractive for the potential use of E4orf1 as a drug to improve glycemic control in the presence of impaired proximal insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

E4orf1 protein reduces the need for endogenous insulin

et al. 2019

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Background E4orf1 protein derived from adenovirus-36 reduces glucose excursion in mice, and lowers endogenous insulin response, suggesting a reduced need for insulin. We tested if the E4orf1-mediated lowering of insulin response is due to increased tissue sensitivity to insulin, reduced ability to produce or release insulin, or a reduced need for insulin release. Methods Experiment 1 : hyperinsulinemic–euglycemic clamps (HEC) and glucose tolerance test (GTT) were performed in high fat fed transgenic mice expressing E4orf1 or non-transgenic littermates ( n = 12 each), for 4 weeks. Experiments 2, 3, and 4 : E4orf1 or null vectors were expressed in rat-pancreatic β-cell line (INS-1) for 72 h, and cells were exposed to varying levels of glucose. Cell lysates and media were collected. Experiment 5 : 3T3L1-preadipocytes that express E4orf1 upon doxycycline induction, or null vector were induced with doxycycline and then exposed to protein transport inhibitor. Supernatant and cell lysate were collected. Experiment 6 : 3T3L1-preadipocytes that express E4orf1 upon doxycycline induction, or null vector were co-cultured with INS-1 cells for 24 h. Media was collected. Results Experiment 1 : E4orf1 transgenic mice cleared glucose faster compared to non-transgenic mice during GTT. HEC showed that E4orf1 did not alter tissue sensitivity to exogenous insulin in mice. Experiments 2, 3, and 4 : in INS1 cells, E4orf1 did not alter Glut2 abundance or Akt activation, suggesting no reduction in glucose sensing or insulin synthesis, respectively. E4orf1 did not influence glucose-stimulated insulin secretion in media by INS1 cells. Experiment 5 : E4orf1 was present in cell lysate, but not in media, indicating it is not a secretory protein. Experiment 6 : INS1 cells released less insulin in media when co-cultured in the presence of E4orf1-expressing 3T3-L1 cells. Conclusions Our studies support the working hypothesis that the E4orf1-mediated lowering of insulin response is not due to increased tissue sensitivity to insulin, or reduced ability to produce or release insulin, but likely to be due to a reduced need for insulin release.

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“…Systematic reviews and meta-analyses of studies in humans show a robust association between the presence of Ad-36 viral antibodies and human obesity [5][6][7][8]. In vitro 3T3-L1 cell infection with Ad-36 enhances adipogenesis leading to increased lipid content, proliferation and higher commitment to adipocyte lineage [6, [9][10][11][12]. Animal experiments have also linked Ad-36 infection with an increase in visceral fat and total body fat, and lower serum cholesterol [4,13,14].…”

Section: Introductionmentioning

confidence: 99%

Adenovirus 36 seropositivity influences the expression of anti-adipogenic lncRNAs GAS5 and MEG3 in adipose tissue obtained from subjects with obesity

Cerda,

Manriquez,

Brito

et al. 2023

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Background Adenovirus 36 (Ad-36) promotes adipogenesis and the development of human obesity. Induction of PPARγ by Ad-36 seems to have a central role in maintenance of adipogenic status. There is limited information about epigenetic mechanisms contributing to this process in human adipose tissue. This study evaluated the expression of lncRNAs (ADINR, GAS5 and MEG3) and miRNAs ((miR-18a and miR-140) involved in adipogenic process in visceral adipose tissue (VAT) of subjects with obesity with previous Ad-36 infection (seropositive) and unexposed (seronegative) obese subjects.Methods Obese individuals were grouped according to seroconversion against Ad-36 (Seropositive: Ad-36[+], n = 29; and Seronegative: Ad-36[-], n = 28). Additionally, a group of lean controls (n = 17) was selected to compare with the obese group. The Ad-36 serology was carried out by ELISA. Biopsies of VAT were obtained during an elective and clinically indicated surgery (bariatric or cholecystectomy). RNA extraction from VAT was performed and the expression of PPARG and non-coding RNAs was evaluated by qPCR.Results Ad-36[+] individuals had lower expression of anti-adipogenic lncRNAs GAS5 (p = 0.016) and MEG3 (p = 0.035) compared with Ad-36[-] obese subjects. Ad-36[+] subjects also presented increased expression of the adipogenic miRNA miR-18a (p = 0.042), which has been reported to be modulated by GAS5 through a RNA sponging mechanism during adipogenic differentiation. Additionally, an inverse correlation of GAS5 with PPARG expression was observed (r= -0.917, p = 0.01).Conclusion Our results suggest the participation of non-coding RNAs implicated in adipogenic process in the long-term maintenance of adipogenic status associated with previous Ad-36 infection, probably through the GAS5/miR-18a axis.

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E4orf1: A protein for enhancing glucose uptake despite impaired proximal insulin signaling

Cited by 14 publications

References 39 publications

Reducing endogenous insulin is linked with protection against hepatic steatosis in mice

Reducing endogenous insulin is linked with protection against hepatic steatosis in mice

E4orf1 protein reduces the need for endogenous insulin

Adenovirus 36 seropositivity influences the expression of anti-adipogenic lncRNAs GAS5 and MEG3 in adipose tissue obtained from subjects with obesity

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