GDF15 negatively regulates RGS16 to impair hepatic lipid metabolism in male mice offspring conceived by in vitro fertilization.

objectivesWe generated an in vitro fertilization and embryo transfer (IVF-ET) mouse model to investigate the molecular mechanism underlying the abnormal lipid metabolism found in IVF-ET offspring.

methodsThe glucose metabolism levels of offspring were assessed by glucose tolerance test (GTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). The lipid metabolism levels were assessed by triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). RNA-seq was performed on liver tissues. mRNA and protein expression of relevant genes was verified by the quantitative real-time PCR and protein immunoblotting. HepG2 cells were transfected with either interfering RNA or overexpression plasmids to investigate the gene functions.

resultsCompared to the control, male IVF-ET offspring showed: 1) higher body, liver, and epididymal white adipose tissue weight; 2) disrupted glucolipid metabolism with abnormal GTT, ITT, and PTT; 3) significantly decreased GDF15 along with increased RGS16. Furthermore, phosphorylation of ERK1/2 and AKT was significantly reduced. In HepG2 cells, knockdown of GDF15 caused an abnormally increased RGS16 and decreased phosphorylation of ERK1/2 and AKT, accompanied by increased lipid deposition. In contrast, overexpression of GDF15 reduced expression of RGS16. Simultaneous knockdown of both GDF15 and RGS16 reversed lipid deposition.

conclusionsDown-regulation of GDF15 results in elevated RGS16, which causes the weakening of the downstream ERK1/2 and AKT phosphorylation, leading to abnormal lipid metabolism in the livers of IVF-ET male offspring. This suggests that the GDF15-RGS16-p-ERK1/2/p-AKT pathway plays a crucial role in liver lipid deposition in IVF-ET male offspring and could be a therapeutic target.