Activation of Browning Adipose Tissues by Placental Growth Factor

Abstract

Background: Gestational diabetes mellitus (GDM) is a type of metabolic disorders. Browning adipose tissue (BAT) activity is reduced which strengthens insulin resistance in GDM. Placenta growth factor (PlGF) is one of the main factors produced by placenta during pregnancy. Once secreted into circulation, it participates in angiogenesis in peripheral tissues. However, whether and how PlGF modulates BAT function is yet unknown. Methods: We recruited 91 nondiabetic pregnant participants and 73 GDM patients. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by Far infrared thermography in the supraclavicular region where classical BAT was located. Primary human preadipocytes isolated from intercapsular BAT were differentiated under different concentrations of PlGF in vitro. Terminally differentiated adipocytes were characterized by qPCR, western blot and oxygen consumption rates by respirometry. Phosphorylation signaling pathways in differentiated cells were dissected using Bio-Plex target assay (Bio-Rad). Cells were exposed with 1 ng PlGF in the presence or absence of 1 nM AMPK inhibitor Compound C to assess UCP-1 expression. Results: Serum levels of PlGF were lower in GDM patients than non GDM controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR, PlGF dose-dependently induced BAT marker expression in differentiated brown adipocytes (BAC) and peaked at 1 ng as evidenced by the increased mRNA expression of UCP-1 and Oxphos. The increased BAT marker expression was further confirmed by western blot in differentiated BAC exposed to 1 ng PlGF. Accordingly, PlGF-exposed BAC showed higher oxygen consumption rates than control and stimulated AMPK phosphorylation. Blockade of AMPK phosphorylation abrogated UCP-1 and Oxphos expression in BAC induced by PlGF. Conclusions: Physically, PlGF improves preadipocyte differentiation into active BAC. Decreased PlGF levels might contribute to the reduced BAC activity in GDM. Disclosure R. Yin: None. J. Zhou: None. C. Zhang: None. C. Yan: None. W. Ma: None. N. Wu: None. D. Zhao: None. Y. Feng: None.