LAUSR

Abstract Metabolic flexibility reflects the ability to switch from lipid to carbohydrate oxidation during insulin stimulation manifested in increased respiratory quotient (∆RQ). Obese adolescent girls with PCOS have metabolic inflexibility compared with their non-PCOS obese peers (JCEM 2018, PMID 29220530). To examine if metabolic inflexibility is also present in lean PCOS or is unique to obese PCOS, we investigated metabolic flexibility in lean and obese women (ages 18-42 yrs.) with PCOS. Data in 24 obese (body mass index, BMI 33.4 ± 4.7 [SD] kg/m2) and 15 lean (BMI 22.7 ± 2.0 kg/m2) PCOS women (diagnosed by the Rotterdam criteria), and 14 obese (BMI 32.5 ± 5.0 kg/m2) and 16 lean (22.9 ± 1.4 kg/m2) control women without PCOS were examined. RQ and lipid oxidation, by indirect calorimetry, were analyzed at fasting and during a hyperinsulinemic-euglycemic clamp. The relationship between metabolic flexibility (assessed as ∆RQ from fasting to hyperinsulinemia) and clamp insulin sensitivity (IS), sex hormones, C-reactive protein (CRP), BMI and leptin concentrations was evaluated. Despite similar BMI and leptin levels, obese PCOS women had lower ∆RQ compared with obese control women (0.07 ± 0.04 vs. 0.11 ± 0.04, p< 0.0001). However, ∆RQ was not different between obese and lean PCOS women, nor was fasting lipid oxidation and suppression in lipid oxidation during hyperinsulinemia. Insulin sensitivity was lower (3.9 ± 1.4 vs. 7.4 ± 2.6 mg/Kg/min per mU/L, p< 0.0001), and CRP and leptin concentrations were higher in obese PCOS vs. lean PCOS (3.34 ± 1.87 vs. 1.29 ± 1.18 mg/L; and 33.6 ± 11.0 vs. 12.4 ± 8.5 ng/L, respectively, all p< 0.05). In the total cohort, ∆RQ correlated with free androgen index (r = -0.359), androstenedione (r = -0.271), and IS (r = 0.452) (all p< 0.05). Multiple regression analysis in the total cohort revealed that the best predictor of metabolic flexibility was PCOS status (partial r = -0.243, p= 0.05) independent of BMI and age. In PCOS women, IS (partial r = 0.503, p= 0.002) and baseline RQ (partial r = -0.489, p= 0.003) explained 46% of the variance in metabolic flexibility with no significant effect of BMI and age. Findings were similar in non-PCOS women (model R2 = 0.750, p= 0.001). Replacing BMI with leptin in the models for PCOS or control women did not change the results. In conclusion, our data suggest that PCOS status, rather than adiposity plays a role in the metabolic inflexibility observed in women with PCOS. It remains to be determined if the lack of a difference in metabolic inflexibility between obese and lean PCOS women applies across the lifespan and holds true in adolescents too, or if metabolic flexibility differs early in the course of PCOS between obese and lean adolescents, but the difference fades as they get older and enter womanhood. Sources of Research Support: Juselius Foundation and Academy of Finland