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Mechanisms behind Lipolytic Catecholamine Resistance of Subcutaneous Fat Cells in the Polycystic Ovarian Syndrome

Departments of Medicine (G.F., M.R., H.W., P.A.) and Gynaecology (I.E.) at Huddinge University Hospital, Karolinska Institute, SE-141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Peter Arner, M.D., Ph.D., Professor, Department of Medicine, M63, Huddinge University Hospital, Karolinska Institutet, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}medhs.ki.se.

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 ß₂-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 ß₂-adrenoceptors, HSL, and the regulatory IIß-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 ß₁-adrenoceptors. Thus, lipolytic catecholamine resistance of sc adipocytes in PCOS is probably attributable to a combination of decreased amounts of ß₂-adrenergic receptors, the regulatory IIß-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.

This work was supported by grants from Åke Wiberg Foundation, Tore Nilsson Foundation, Swedish Medical Society and Foundation for Scientific Work in Diabetes, Swedish Research Council, Swedish Heart and Lung Association, Swedish Diabetes Association, and Novo Nordic Fund.

G.F. and M.R. contributed equally to the study.

Abbreviations: AR, Adrenergic receptor; BMI, body mass index; HOMA, insulin sensitivity index; HSL, hormone-sensitive lipase; PCOS, polycystic ovarian syndrome; PKA, protein kinase A; PKAcat, the catalytic region of PKA.

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