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Insulin signaling regulates whole-body glucose and lipid homeostasis. Upon stimulation by insulin, signals are transduced from the insulin receptor to propagate two main downstream branches, the PI3K-Akt pathway and the Ras-MAPK pathway. These orchestrate a plethora of biological functions on growth and metabolism, such as proliferation, differentiation, survival, glucose uptake and lipolysis.

Christine M. Kusminski et al. studied the different branches of the insulin signaling pathway by generating and characterizing an inducible mouse model of E4orf1 expression in adipocytes (E4orf1 Tg mice). Expression of the 14-kDa adenoviral polypeptide resulted in 'insulin-sparing' characteristics, i.e. during glucose tolerance tests, E4orf1 Tg mice exhibited a profoundly lower transient insulin spike compared to WT mice. This phenomenon arises from activation of a Ras-ERK-MAPK signaling pathway that enhances insulin-independent p-Akt activation. By this way, E4orf1 increases Glut4 translocation to the plasma membrane and glucose uptake even in the absence of insulin. At the same time E4orf1 seems to inhibit the PI3K-Akt branch of the insulin signaling pathway.

The authors found a pronounced phenotype. Under high fat diet, E4orf1 Tg mice showed lower body-weight gain and inflamed white adipose tissue (WAT) with enhanced macrophage infiltration, increased inflammatory markers and fibrosis. These observations indicate 'unhealthy' white adipose tissue expansion during the onset of diet-induced obesity. Consistently, E4orf1 Tg mice harbored markedly lower circulating levels of adiponectin, a typical hallmark of metabolically unhealthy WAT.



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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

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Brandon Panaro
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
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