A Unique Defect in the Regulation of Visceral Fat Cell Lipolysis in the Polycystic Ovary Syndrome as an Early Link to Insulin Resistance
- Ingvar Ek1,
- Peter Arner2,
- Mikael Rydén2,
- Cecilia Holm3,
- Anders Thörne4,
- Johan Hoffstedt2 and
- Hans Wahrenberg2
- 1Department of Gynecology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
- 2Department of Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
- 3Department of Cell and Molecular Biology, Lund University, Lund, Sweden
- 4Department of Surgery, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
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). Catecholamine-induced 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 Iα components of PKA. In contrast, the regulatory RIIβ 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.
Address correspondence and reprint requests to Peter Arner, MD, Karolinska Institutet, Department of Medicine, CME, 141 86 Stockholm, Sweden. E-mail:.
Received for publication 19 April 2001 and accepted in revised form 31 October 2001.
8bcAMP, 8-bromocyclic AMP; CT, computer tomography; dcAMP, dibutyryl cAMP; EC50, half-maximum effect; HSL, hormone sensitive lipase; OD, optical density; PCOS, polycystic ovary syndrome; PKA, protein kinase A; SHBG, sex hormone-binding globulin; WHR, waist-to-hip ratio.