Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation

Abstract

Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms “oxidative phosphorylation”, “ribosome”, “gap junction”, “PPAR signaling pathway”, and “focal adhesion” were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.

Integrated Remodeling of Gut–Liver Metabolism Induced by Moderate Protein Restriction Contributes to Improvement of Insulin Sensitivity

“…Hepatic transcriptome data (accession number SUB2170304), representing 12, 28 days old, castrated male growing pigs with an initial BW of 9.57 ± 0.64 kg offered 20% CP of diet (CON) or 14% CP of diet for 30 days (the feed intake and final BW were not reported), were downloaded from the NIH Short Read Archive database. This data represented the liver transcriptomic adaption upon moderate PR.…”

Implications of Insulin-Like Growth Factor-1 in Skeletal Muscle and Various Diseases

“…Circulating IGF-1 is controlled by members of the IGF binding protein family (IGFBP-1~6) and acid-labile subunit (ALS). GH, insulin, and nutritional status are responsible for the secretion of IGF-1 [44,45]. The maintenance of hypertrophic phenotype by IGF-1Ea involves also the activation of AMPK pathways, a factor involved in the maintenance of whole-body energy balance and an "energy sensor" controlling glucose and lipid metabolism [46].…”

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

“…Besides JAK2, other upstream regulators of hepatic IGF-1 may mediate its effects, such as FGF21, PPARγ, and components of the hedgehog signaling pathway including Smoothened (66)(67)(68). Furthermore, recent clinical studies have shown ω-3 supplementation and baclofen, a β-p-chlorophenyl derivative of γ-aminobutyric acid (GABA), in increasing plasma IGF-1 concentrations to varying extent (69)(70)(71).…”