Reduced LPL and subcutaneous lipid storage capacity are associated with metabolic syndrome in postmenopausal women with obesity

Menopause is commonly associated with weight gain, and the accumulation of body fat in the abdominal region, which independently increases risk for type 2 diabetes mellitus (T2DM), metabolic syndrome (MSyn) and subsequent cardiovascular disease (CVD) 1. While weight gain and ageing are strong risk factors for MSyn, not all overweight and obese individuals develop these metabolic abnormalities. A range of metabolically healthy and unhealthy phenotypes was shown to exist across the continuum of obesity, with some classified as having metabolic healthy obesity or obesity in the absence of metabolic dysfunction and others as having unhealthy obesity 2, 3. Analysis of NHANES data found that the age‐standardized prevalence of the metabolically abnormal phenotype [defined by ≥2 of the criteria for MSyn, including elevated waist circumference, blood pressure (BP), triglycerides (TG), glucose (FPG) and reduced high‐density lipoprotein cholesterol (HDL‐C) 4, as well as high‐sensitive C‐reactive protein and homeostasis model assessment‐estimated insulin resistance (HOMA‐IR)] was 65% in obese, 43% in overweight and 21% in normal women, whereas 35% of obese, 57% of overweight and 79% of normal weight women were metabolically healthy, as defined by <2 risk factors 5. The presence of ≥3 or more of five of these metabolic abnormalities constitutes MSyn, a clustering of risk factors that enhances risk for CVD mortality in postmenopausal women to a greater extent than in men or premenopausal women 6; therefore, identifying potential mechanisms other than obesity, sedentary behaviour and ageing that result in metabolic dysfunction may provide insight into therapeutic strategies to prevent the development of T2DM and CVD complications in older women with obesity 4. The limited capacity to expand subcutaneous adipose tissue (SAT), or the ‘adipose tissue expandability hypothesis’ as proposed by Danforth 7, posits that there is a finite limit to which an individual's adipose tissue can expand to fulfil its role as an organ for lipid storage. Once this capacity is exceeded, any excess circulating triacylglycerol (TG‐FFA) will be deposited in undesirable or ectopic fat depots, including visceral adipose tissue (VAT), liver and skeletal muscle, which are associated with insulin resistance and metabolic dysfunction 7, 8, 9. Lipoprotein lipase (LPL) is the rate‐limiting enzyme for the uptake and storage of TG‐FFAs in adipose tissue, and genes related to fat cell expansion and lipid storage such as LPL, PPARɣ and fatty acid synthase are higher in SAT of insulin sensitive than resistant subjects 9, 10. Intervention studies show that thiazolidinedione (TZD) administration, by upregulating PPARɣs causes SAT hypertrophy and reduces VAT and intrahepatic fat to improve lipid and glucose metabolism in patients with obesity and T2DM 11, and that PPARɣ2 activation increases adipogenesis and insulin sensitivity 12. This supports the hypothesis that the pathways involved in lipid storage in subcutaneous and ectopic sites play a role in the insulin resistance‐associated metabolic consequences of obesity. This is inferred from the work of others 9, 13, 14, 15, 16, and our recent research that showed in a select cohort of sedentary, older women with obesity higher adipose tissue LPL activity (AT‐LPLA) in those with a low, compared with a higher ratio of VAT/VAT + SAT area is associated with larger adipocyte size and SAT area, as well as fewer metabolic abnormalities 17. It is the aim of this study to extend the generalizability of our prior finding to MSyn by testing the hypothesis that lower AT‐LPLA will be associated with a limited capacity for subcutaneous adipocyte expansion, greater visceral fat accumulation and MSyn in postmenopausal women who are overweight and obese.