A possible role for AMP-activated protein kinase activated by metformin and AICAR in human granulosa cells

Abstract

BackgroundWomen with polycystic ovary syndrome (PCOS) are generally insulin- resistant and are consequently often treated with metformin. We investigated the effect of metformin and AICAR on the AMP-activated protein kinase (AMPK) pathway.MethodsWe evaluated the effects of 5-amino-imidazole-4-carboxyamide-1- beta-D-ribofuranoside (AICAR) and metformin on tumor necrosis factor (TNF)-alpha- stimulated chemokine production in human granulosa cells. The phosphorylations of AMPK, I-kappaB, 4E-BP-1, p70S6K were analyzed by western immunoblotting.ResultsAICAR and metformin markedly reduced the IL-8 and GROalpha production induced by TNF-alpha. AICAR and metformin also reduced the TNF-alpha-induced phosphorylation of I-kappaB. The phosphorylations of I-kappaB, 4EBP-1, p70S6K were inhibited via an AMPK-dependent signal transduction.ConclusionsThese results suggest that metformin promotes granulosa cell function by reducing a TNF-alpha- and chemokine-mediated inflammatory reaction through an AMPK-dependent pathway. These finding may have implications for metformin’s actions during the treatment of PCOS with metformin.

Baicalin ameliorates polycystic ovary syndrome through AMP-activated protein kinase

“…Moreover, AMPK was shown to reduce the activity of NF-κB and the levels of the pro-inflammatory cytokine TNFα [25]. Metformin, the agonist of AMPK, could attenuate TNFα-and chemokinemediated inflammatory responses and granulocyte dysfunction in an AMPK-dependent manner [26]. Previous studies have suggested that BAL could upregulate AMPK [27] and thus we verified whether activation of AMPK participated in the effects of BAL on PCOS.…”

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…As a result, the ability of MF to improve energy metabolism, prevent lipotoxicity and restore the redox balance in the ovaries is another mechanism of its beneficial effect on folliculogenesis and the ovulatory cycle in PCOS. In human granulosa cells, through AMPK-dependent mechanisms, MF suppresses the tumor necrosis factor-α (TNF-α)-induced production of pro-inflammatory cytokines, interleukin-8 and chemokine CXCL1/GROα [ 303 ]. The other AMPK activators, such as AICAR and Baicalin, also reduce TNF-α- and chemokine-mediated inflammatory responses in ovarian cells [ 303 , 304 ].…”

Vitamin D3 regulates steroidogenesis in granulosa cells through AMP‐activated protein kinase (AMPK) activation in a mouse model of polycystic ovary syndrome

“…15,59 Tosca et al showed that AMPK activation through Aicar could decrease the abundance of HSD3B, CYP11A1, and STAR proteins and reduced estradiol and progesterone secretion in bovine granulosa cells. However, the involvement of AMPK activation in steroid secretion in normal granulosa cells of some species is reported in previous studies that were stimulated by Aicar and insulin sensitizer drugs like metformin.…”

“…However, the involvement of AMPK activation in steroid secretion in normal granulosa cells of some species is reported in previous studies that were stimulated by Aicar and insulin sensitizer drugs like metformin. 15,59 Tosca et al showed that AMPK activation through Aicar could decrease the abundance of HSD3B, CYP11A1, and STAR proteins and reduced estradiol and progesterone secretion in bovine granulosa cells. 18 Obtained findings in the present study also showed that increased phosphorylation levels of AMPK through vitamin D3 treatment could decrease mRNA expression levels of aromatase, 3β-HSD, Cyp11a1, and StAR genes in granulosa cells of PCOS mice.…”