The etiology of polycystic ovary syndrome (PCOS) is unknown. However, PCOS has a strong resemblance to the insulin resistance (metabolic) syndrome, where an increased rate of visceral fat cell lipolysis is believed to play a pathophysiological role. We hypothesized that primary defects in visceral lipolysis might also exist in PCOS. Ten young, nonobese, and otherwise healthy PCOS women were compared with 13 matched control women. In vitro lipolysis regulation and stoichiometric properties of the final step in lipolysis activation, namely the protein kinase A (PKA)-hormone sensitive lipase (HSL) complex, were investigated in isolated visceral (i.e., omental) fat cells. Body fat distribution and circulating levels of insulin, glucose, and lipids were normal in PCOS women. However, in vivo insulin sensitivity was slightly decreased (P ؍ 0.03). Catecholamineinduced adipocyte lipolysis was markedly (i.e., about twofold) increased in PCOS women due to changes at the postreceptor level, although there was no change in the antilipolytic properties of visceral fat cells. Western blot analyses of visceral adipose tissue showed twofold increased levels of the catalytic and the regulatory I␣ components of PKA. In contrast, the regulatory RII component of PKA was almost 50% decreased in visceral adipose tissue in PCOS women. Recent studies on genetically modified mice have shown that a similar transition in the regulatory PKA units induces an increased lipolytic response to catecholamines. Further analysis showed that the level of HSL-short, an enzymatically inactive splice form of HSL, was decreased in PCOS (P < 0.01). The altered lipolysis in PCOS is different from that observed in visceral fat cells in the insulin resistance syndrome that occurs at the level of adrenergic receptors. We concluded that increased catecholamine-induced lipolysis in visceral fat cells may be due to unique alterations in the stoichiometric properties of the adipose PKA-HSL holoenzymes. This could be an early and possibly primary lipolysis defect in PCOS.
Lipolytic catecholamine resistance in sc fat cells is observed in polycystic ovarian syndrome (PCOS). The mechanisms behind this lipolysis defect were explored in vitro; sc fat cells were obtained from 10 young, nonobese PCOS women and from 14 matched, healthy control women. Fasting plasma glycerol levels were reduced by one third in PCOS (P < 0.05). Adipocytes of PCOS women were about 25% larger than in the controls (P < 0.05) and had 40% reduced noradrenaline-induced lipolysis (P < 0.05), which could be attributed to a 10-fold decreased beta(2)-adrenoceptor sensitivity (P < 0.05) and low ability of cAMP to activate the protein kinase A (PKA)/hormone-sensitive lipase (HSL) complex (P < 0.05). In PCOS, the adipocyte protein content of beta(2)-adrenoceptors, HSL, and the regulatory II beta-component of PKA were 70%, 55%, and 25% decreased, respectively (P < 0.001); but there was no change in the amount of the catalytic subunit of PKA or of beta(1)-adrenoceptors. Thus, lipolytic catecholamine resistance of sc adipocytes in PCOS is probably attributable to a combination of decreased amounts of beta(2)-adrenergic receptors, the regulatory II beta-component of PKA, and HSL. This may cause low in vivo lipolytic activity and enlarged sc fat cell size and promote later development of obesity in PCOS.
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