Metformin Treatment May Increase Omentin-1 Levels in Women With Polycystic Ovary Syndrome

OBJECTIVE

Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome. Decreased omentin-1 levels are associated with obesity and diabetes. To study the effects of metformin treatment on omentin-1 levels in PCOS subjects and effects of omentin-1 on in vitro migration and angiogenesis.

RESEARCH DESIGN AND METHODS

Serum omentin-1 was measured by ELISA. Angiogenesis was assessed by studying capillary tube formation in human microvascular endothelial cells (HMEC-1) on growth factor reduced Matrigel. Endothelial cell migration assay was performed in a modified Boyden chamber. Nuclear factor-κB (NF-κB) was studied by stably transfecting HMEC-1 cells with a cis-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-κB binding sites. Akt phosphorylation was assessed by Western blotting.

RESULTS

Serum omentin-1 was significantly lower in PCOS women (P < 0.05). After 6 months of metformin treatment, there was a significant increase in serum omentin-1 (P < 0.01). Importantly, changes in hs-CRP were significantly negatively correlated with changes in serum omentin-1 (P = 0.036). In vitro migration and angiogenesis were significantly increased in serum from PCOS women (P < 0.01) compared with matched control subjects; these effects were significantly attenuated by metformin treatment (P < 0.01) plausibly through the regulation of omentin-1 levels via NF-κB and Akt pathways. CRP and VEGF induced in vitro migration, and angiogenesis was significantly decreased by omentin-1.

CONCLUSIONS

Increases in omentin-1 levels may play a role but are not sufficient to explain the decreased inflammatory and angiogenic effects of sera from metformin-treated PCOS women.Polycystic ovary syndrome (PCOS) is a proinflammatory state associated with type 2 diabetes, visceral obesity, and cardiovascular complications, features of the metabolic syndrome (1–5). The metabolic syndrome is associated with accumulation of visceral adipose tissue. Visceral adipose tissue produces cytokines termed “adipokines” implicated in the pathogenesis of diabetes and atherosclerosis (6–9).Omentin-1 has been described as a novel adipokine preferentially produced by visceral adipose tissue. In vitro experiments revealed that treatment with recombinant omentin-1 enhances insulin-stimulated glucose uptake in human adipocytes. Also, omentin-1 was shown to trigger Akt signaling in both the absence and presence of insulin (10,11). Additionally, omentin plasma levels and omentin gene expression in visceral adipose tissue are decreased in obesity (12). Recently, we have reported novel data showing a significant decrease of adipose tissue and circulating omentin-1 levels in overweight PCOS women (13). Thus, given the above functions of omentin-1, increasing omentin-1 levels in PCOS women may alleviate cardiometabolic dysfunction in these women.We studied the effects of metformin treatment on omentin-1 levels in PCOS subjects and effects of omentin-1 and serum on in vitro migration and angiogenesis. Researchers have used serum to perform functional experiments in endothelial, cardiac, and neural cells (14–16). Finally, given the link between inflammation and angiogenesis (17), we explored nuclear factor-kappaB (NF-κB), Erk1/2, and Akt pathways, important regulators of inflammation and angiogenesis (18,19).