Limits...
E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.

Kusminski CM, Gallardo-Montejano VI, Wang ZV, Hegde V, Bickel PE, Dhurandhar NV, Scherer PE - Mol Metab (2015)

Bottom Line: At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge.Nevertheless, they are protected from diet-induced hepatic steatosis.The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

View Article: PubMed Central - PubMed

Affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT

Background/purpose: Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism.

Methods: We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes.

Results: Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events.

Conclusion: We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

No MeSH data available.


Related in: MedlinePlus

In vivo mechanistic action of E4orf1 in the white adipocyte. E4orf1 induction in WAT promotes inflammation, fibrosis, hypoxia and an increase in expression of several collagens. At the level of the white adipocyte, in the presence of excess insulin, the classical insulin signaling transduction pathway is activated to enhance p-Akt. In the absence of insulin, an induction in E4orf1 within the adipocyte can preserve activation of the insulin signaling pathway by triggering a Ras-ERK-MAPK branch of signaling that ultimately enhances p-Akt expression. Consequently at the whole-body level, E4orf1-Tg mice exhibit reduced body-weight gain under metabolic challenge, an increase in fasting-induced lipolysis, reduced adiponectin levels, protection from HFD-induced hepatic steatosis, in addition to key “insulin-sparing” effects during glucose tolerance testing.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4588421&req=5

fig6: In vivo mechanistic action of E4orf1 in the white adipocyte. E4orf1 induction in WAT promotes inflammation, fibrosis, hypoxia and an increase in expression of several collagens. At the level of the white adipocyte, in the presence of excess insulin, the classical insulin signaling transduction pathway is activated to enhance p-Akt. In the absence of insulin, an induction in E4orf1 within the adipocyte can preserve activation of the insulin signaling pathway by triggering a Ras-ERK-MAPK branch of signaling that ultimately enhances p-Akt expression. Consequently at the whole-body level, E4orf1-Tg mice exhibit reduced body-weight gain under metabolic challenge, an increase in fasting-induced lipolysis, reduced adiponectin levels, protection from HFD-induced hepatic steatosis, in addition to key “insulin-sparing” effects during glucose tolerance testing.

Mentions: By taking advantage of the properties of E4orf1, we generated and validated an inducible mouse model that allows us to alter the classical signaling events in the distal branches of the insulin signal transduction pathway in adipose tissue, in an insulin-independent manner. The phenotypic outcome in vivo of such a perturbation results in the adipose tissue-specific E4orf1 transgenic mouse (the E4orf1-Tg mouse) exhibiting lower body-weight gain under metabolically challenging conditions and ‘insulin-sparing’ characteristics during glucose tolerance tests. Transgenic mice also exhibit reduced circulating adiponectin levels, inflamed and fibrotic WAT; however, the mice are protected from diet-induced hepatic steatosis. This model, therefore, defies many expectations regarding adiposity, healthy state of adipose tissue, adiponectin levels and insulin sensitivity. Ex vivo analyses revealed that E4orf1 promotes up-regulation of p-Akt expression in adipose tissues in the absence of insulin. Furthermore, microarray analyses pinpointed that specifically under metabolic challenge, enhanced Ras-ERK-MAPK signaling in E4orf1-Tg sWAT could serve as a potential alternative route to bypass classical insulin signaling events. Interestingly, insulin negatively regulates E4orf1 protein expression in sWAT and, moreover, stimulates the intracellular re-localization of E4orf1 protein from cytosolic to nuclear compartments. Finally under metabolic challenge, E4orf1-Tg mice exhibit whitening of BAT, as a reduction in transcriptional profile of classical browning markers, in addition to enlarged lipid-laden hypertrophic adipocytes was evident. Nevertheless, glucose tolerance remained normal in these mice. Taken together, Figure 6 highlights the in vivo action of E4orf1 in adipocytes.


E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.

Kusminski CM, Gallardo-Montejano VI, Wang ZV, Hegde V, Bickel PE, Dhurandhar NV, Scherer PE - Mol Metab (2015)

In vivo mechanistic action of E4orf1 in the white adipocyte. E4orf1 induction in WAT promotes inflammation, fibrosis, hypoxia and an increase in expression of several collagens. At the level of the white adipocyte, in the presence of excess insulin, the classical insulin signaling transduction pathway is activated to enhance p-Akt. In the absence of insulin, an induction in E4orf1 within the adipocyte can preserve activation of the insulin signaling pathway by triggering a Ras-ERK-MAPK branch of signaling that ultimately enhances p-Akt expression. Consequently at the whole-body level, E4orf1-Tg mice exhibit reduced body-weight gain under metabolic challenge, an increase in fasting-induced lipolysis, reduced adiponectin levels, protection from HFD-induced hepatic steatosis, in addition to key “insulin-sparing” effects during glucose tolerance testing.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588421&req=5

fig6: In vivo mechanistic action of E4orf1 in the white adipocyte. E4orf1 induction in WAT promotes inflammation, fibrosis, hypoxia and an increase in expression of several collagens. At the level of the white adipocyte, in the presence of excess insulin, the classical insulin signaling transduction pathway is activated to enhance p-Akt. In the absence of insulin, an induction in E4orf1 within the adipocyte can preserve activation of the insulin signaling pathway by triggering a Ras-ERK-MAPK branch of signaling that ultimately enhances p-Akt expression. Consequently at the whole-body level, E4orf1-Tg mice exhibit reduced body-weight gain under metabolic challenge, an increase in fasting-induced lipolysis, reduced adiponectin levels, protection from HFD-induced hepatic steatosis, in addition to key “insulin-sparing” effects during glucose tolerance testing.
Mentions: By taking advantage of the properties of E4orf1, we generated and validated an inducible mouse model that allows us to alter the classical signaling events in the distal branches of the insulin signal transduction pathway in adipose tissue, in an insulin-independent manner. The phenotypic outcome in vivo of such a perturbation results in the adipose tissue-specific E4orf1 transgenic mouse (the E4orf1-Tg mouse) exhibiting lower body-weight gain under metabolically challenging conditions and ‘insulin-sparing’ characteristics during glucose tolerance tests. Transgenic mice also exhibit reduced circulating adiponectin levels, inflamed and fibrotic WAT; however, the mice are protected from diet-induced hepatic steatosis. This model, therefore, defies many expectations regarding adiposity, healthy state of adipose tissue, adiponectin levels and insulin sensitivity. Ex vivo analyses revealed that E4orf1 promotes up-regulation of p-Akt expression in adipose tissues in the absence of insulin. Furthermore, microarray analyses pinpointed that specifically under metabolic challenge, enhanced Ras-ERK-MAPK signaling in E4orf1-Tg sWAT could serve as a potential alternative route to bypass classical insulin signaling events. Interestingly, insulin negatively regulates E4orf1 protein expression in sWAT and, moreover, stimulates the intracellular re-localization of E4orf1 protein from cytosolic to nuclear compartments. Finally under metabolic challenge, E4orf1-Tg mice exhibit whitening of BAT, as a reduction in transcriptional profile of classical browning markers, in addition to enlarged lipid-laden hypertrophic adipocytes was evident. Nevertheless, glucose tolerance remained normal in these mice. Taken together, Figure 6 highlights the in vivo action of E4orf1 in adipocytes.

Bottom Line: At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge.Nevertheless, they are protected from diet-induced hepatic steatosis.The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

View Article: PubMed Central - PubMed

Affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.

ABSTRACT

Background/purpose: Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism.

Methods: We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes.

Results: Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events.

Conclusion: We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

No MeSH data available.


Related in: MedlinePlus