1. Leucine facilitates insulin signaling through a Gαi protein-dependent signaling pathway in hepatocytes.
- Author
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Yang X, Mei S, Wang X, Li X, Liu R, Ma Y, Hao L, Yao P, Liu L, Sun X, Gu H, Liu Z, and Cao W
- Subjects
- Animals, Diabetes Mellitus metabolism, Gene Silencing, Gluconeogenesis, Glucose metabolism, Humans, Mice, Models, Biological, Obesity metabolism, Phosphorylation, RNA, Small Interfering metabolism, Signal Transduction, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Hepatocytes cytology, Insulin metabolism, Leucine metabolism
- Abstract
In this study, we addressed the direct effect of leucine on insulin signaling. In investigating the associated mechanisms, we found that leucine itself does not activate the classical Akt- or ERK1/2 MAP kinase-dependent signaling pathways but can facilitate the insulin-induced phosphorylations of Akt(473) and ERK1/2 in a time- and dose-dependent manner in cultured hepatocytes. The leucine-facilitated insulin-induced phosphorylation of Akt at residue 473 was not affected by knocking down the key component of mTORC1 or -2 complexes but was blocked by inhibition of c-Src (PP2), PI3K (LY294002), Gαi protein (pertussis toxin or siRNA against Gαi1 gene, or β-arrestin 2 (siRNA)). Similarly, the leucine-facilitated insulin activation of ERK1/2 was also blunted by pertussis toxin. We further show that leucine facilitated the insulin-mediated suppression of glucose production and expression of key gluconeogenic genes in a Gαi1 protein-dependent manner in cultured primary hepatocytes. Together, these results show that leucine can directly facilitate insulin signaling through a Gαi protein-dependent intracellular signaling pathway. This is the first evidence showing that macronutrients like amino acid leucine can facilitate insulin signaling through G proteins directly.
- Published
- 2013
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