Research Article: The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control

Date Published: June 5, 2019

Publisher: Public Library of Science

Author(s): Catia M. Pereira, Renato Filev, Francisco P. Dubiela, Bruna B. Brandão, Claudio M. Queiroz, Raissa G. Ludwig, Debora Hipolide, Beatriz M. Longo, Luiz E. Mello, Marcelo A. Mori, Beatriz A. Castilho, Shree Ram Singh.

http://doi.org/10.1371/journal.pone.0217287

Abstract

IMPACT, a highly conserved protein, is an inhibitor of the eIF2α kinase GCN2. In mammals, it is preferentially expressed in neurons. Knock-down of IMPACT expression in neuronal cells increases basal GCN2 activation and eIF2α phosphorylation and decreases translation initiation. In the mouse brain, IMPACT is particularly abundant in the hypothalamus. Here we describe that the lack of IMPACT in mice affects hypothalamic functions. Impact-/- mice (Imp-KO) are viable and have no apparent major phenotypic defect. The hypothalamus in these animals shows increased levels of eIF2α phosphorylation, as expected from the described role of IMPACT in inhibiting GCN2 and from its abundance in this brain region. When fed a normal chow, animals lacking IMPACT weight slightly less than wild-type mice. When fed a high-fat diet, Imp-KO animals gain substantially less weight due to lower food intake when compared to wild-type mice. STAT3 signaling was depressed in Imp-KO animals even though leptin levels were identical to the wild-type mice. This finding supports the observation that Imp-KO mice have defective thermoregulation upon fasting. This phenotype was partially dependent on GCN2, whereas the lean phenotype was independent of GCN2. Taken together, our results indicate that IMPACT contributes to GCN2-dependent and -independent mechanisms involved in the regulation of autonomic functions in response to energy availability.

Partial Text

The protein IMPACT was first identified as the product of an imprinted gene in mice, containing a so-called “ancient domain” due to its strong similarity with bacterial proteins [1]. Another domain of the IMPACT protein and of its yeast ortholog, Yih1, shares sequence similarity with a region present in GCN2, a kinase that regulates protein synthesis. Several studies performed in mammalian cells as well as in yeast have indicated that IMPACT/Yih1 inhibits the activity of GCN2 [2–7].

We have shown here that the protein IMPACT contributes to the weight gain and body temperature homeostasis in mice.

 

Source:

http://doi.org/10.1371/journal.pone.0217287

 

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