Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance markers in women of varying age and adiposity

Markers of adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m2). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat samples. AT dysfunction markers were correlated with most lipid-lipoprotein levels such as TAGs (-0.36<rho<0.46; 0.0005<p<0.05), except OME CD68 expression which was negatively related to HDL-cholesterol. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR (-0.60<rho<-0.63; p<0.0001), while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables (0.39<rho<0.59; p<0.01). Multiple regression analyses including these markers and triacylglycerol (TAG) levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR (partial R2=0.31-0.33; 0.000<p<0.005) in the model with TAGs and CD68 expression. However, the contribution of the A/L ratio was supplanted by adipose cell size in the model where the latter replaced TAGs. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Taken together, our results show that adipocyte hypertrophy combined with reduced A/L ratio was related to increased IR, suggesting an independent contribution of both markers to the variance of cardiometabolic risk.

Adipose cell size changes are associated with a drastic actin remodeling

Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes. In the present study, we demonstrate that changes in adipocyte size correlate with a drastic remodeling of the actin cytoskeleton. Expansion of primary adipocytes following 2 weeks of high-fat diet (HFD)-feeding in C57BL6/J mice was associated with a drastic increase in filamentous (F)-actin as assessed by fluorescence microscopy, increased Rho-kinase activity, and changed expression of actin-regulating proteins, favoring actin polymerization. At the same time, increased cell size was associated with impaired insulin response, while the interaction between the cytoskeletal scaffolding protein IQGAP1 and insulin receptor substrate (IRS)-1 remained intact. Reversed feeding from HFD to chow restored cell size, insulin response, expression of actin-regulatory proteins and decreased the amount of F-actin filaments. Together, we report a drastic cytoskeletal remodeling during adipocyte expansion, a process which could contribute to deteriorating adipocyte function.

Adipose cell size: importance in health and disease

Adipose tissue is necessary to harbor energy. To handle excess energy, adipose tissue expands by increasing adipocyte size (hypertrophy) and number (hyperplasia). Here, we have summarized the different experimental techniques used to study adipocyte cell size and describe adipocyte size in relation to insulin resistance, type 2 diabetes, and diet interventions. Hypertrophic adipocytes have an impaired cellular function, and inherent mechanisms restrict their expansion to protect against cell breakage and subsequent inflammation. Reduction of large fat cells by diet restriction, physical activity, or bariatric surgery therefore is necessary to improve cellular function and health. Small fat cells may also be dysfunctional and unable to expand. The distribution and function of the entire cell size range of fat cells, from small to very large fat cells, are an important but understudied aspect of adipose tissue biology. To prevent dysmetabolism, therapeutic strategies to expand small fat cells, recruit new fat cells, and reduce large fat cells are needed.

Citrus Flavonoid Effects on Obesity

The increased prevalence of obesity in recent decades has sparked tremendous concern worldwide. Obesity, a chronic disease that increases the risk for a myriad of diseases including diabetes, hypertension, cardiovascular diseases, as well as certain types of cancers, results from a persistent excess of energy intake versus energy expenditure and is characterized by an increase in both adipose cell size and number. Treatments to date consist of medications that cause various adverse side effects. This has led to the recent shift in focus towards investigating natural alternatives to treat obesity. The use of phytochemicals as a safe and natural alternative to treat obesity is under current investigation as citrus flavonoids haven been shown to monitor energy intake versus expenditure, regulate lipid metabolism and adipose tissue, and inhibit amylase function.