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

Author(s):Show less -

Pereira, Catia M. ^[1] ; Filev, Renato ^{[2, 3]} ; Dubiela, Francisco P. ^[4] ; Brandao, Bruna B. ^{[5, 6]} ; Queiroz, Claudio M. ^[7] ; Ludwig, Raissa G. ^[8] ; Hipolide, Debora ^[4] ; Longo, Beatriz M. ^[2] ; Mello, Luiz E. ^[2] ; Mori, Marcelo A. ^{[5, 8]} ; Castilho, Beatriz A. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Escola Paulista Med, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Physiol, Escola Paulista Med, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Dept Psychiat, Escola Paulista Med, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Dept Psychobiol, Escola Paulista Med, Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Biophys, Escola Paulista Med, Sao Paulo - Brazil

^[6] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02115 - USA

^[7] Univ Fed Rio Grande do Norte, Inst Brain, Natal, RN - Brazil

^[8] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

• Document type: Journal article
• Source: PLoS One; v. 14, n. 6 JUN 5 2019.
• Web of Science Citations: 0

Abstract

IMPACT, a highly conserved protein, is an inhibitor of the eIF2 alpha kinase GCN2. In mammals, it is preferentially expressed in neurons. Knock-down of IMPACT expression in neuronal cells increases basal GCN2 activation and eIF2 alpha 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 eIF2 alpha 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. (AU)

• FAPESP's process: 09/52047-5 - Translational regulation mediated by elF2 in eukaryotes
• Grantee: Beatriz Amaral de Castilho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/04079-8 - Identification of mechanisms responsible for the beneficial effects of caloric restriction
• Grantee: Bruna Brasil Brandao
• Support Opportunities: Scholarships in Brazil - Doctorate