Regulation and Role of Human Resistin in Diabetes during Pregnancy

Abstract

Diabetes during pregnancy affects placental function, which impacts fetal development and the long-term health of offspring. Resistin is a peptide hormone originally discovered in mice as an adipocyte-derived factor that induced insulin resistance. Unlike rodent, human resistin is primarily secreted by monocytes or macrophages. Resistin may act differently in humans, which remains unclear. The present study examined the effects of maternal diabetes on fetal resistin levels and the actions of human resistin in placenta mitochondrial biogenesis pathway. Concentrations of human resistin in cord sera were higher in diabetic pregnancies (67 ng/ml, n=42) compared to healthy controls (50 ng/ml, n=81, P< 0.05), and correlated (r=0.4, P=0.002) with a measure of maternal glycemia (glucose concentration 2 h post challenge). Resistin mRNA was abundant in cord blood mononuclear cells (CBMCs). Secretion of resistin from cultured CBMCs was increased in response to high glucose (25 mM) treatment. Exposing placental trophoblastic cells (BeWo cells) or human placental explant to resistin decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as the abundance of mitochondria transcription factor A (TFAM). In human term placentae, the levels of PGC-1α promotor methylation were positively correlated with cord blood resistin concentrations (r= 0.45, p=0.04, n=16). In summary, we have shown that resistin is increased in the fetal circulation during diabetic pregnancy and that this potentially reflects the response of monocytes/macrophages to hyperglycemia and metabolic stresses associated with diabetic pregnancy. In addition, human resistin has the capacity to decrease mitochondrial biogenesis by affecting the epigenetic regulation of PGC-1α expression. Thus, increased exposure to resistin may contribute to mitochondrial dysfunction and long-term aberrant energy metabolism characteristic of the offspring of diabetic pregnancies. Disclosure S. Jiang: None. A.M. Teague: None. J.B. Tryggestad: None. T. Lyons: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc..