Early studies reported that the size of adipose cells correlates with insulin resistance. However, a recent study comparing moderately obese, sensitive and resistant subjects, with comparable body mass index (BMI, 30), did not detect any significant difference in the size of the large cells, but rather a smaller proportion of large cells in the resistant subjects, suggesting impaired adipogenesis. We hypothesize that a decreased proportion, rather than the size, of large adipose cells is also associated with insulin resistance in lean individuals. Thirty-five leaner (BMI 18 34) subjects who were healthy, but first degree relatives of type 2 diabetics, were recruited. Insulin sensitivity was measured by euglycemic, hyperinsulinemic clamp. Needle biopsies of abdominal subcutaneous fat were assayed for adipose cell size by fitting the cell size distribution with two exponentials and a Gaussian function. The fraction of large cells was defined as the area of the Gaussian peak and the size of the large cells was defined as its center (cp). Glucose infusion rate and cp were negatively correlated, but insulin sensitivity and the proportion of large cells were not correlated. BMI and cp were also strongly correlated, but a relationship of modest correlation between cell size and insulin resistance was still significant after correcting for BMI. In contrast to moderately obese subjects, in lean subjects both BMI and the size of the large adipose cells predict the degree of insulin resistance;no correlation is found between the proportion of large adipose cells and insulin resistance. Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell-size distribution, body fat, and insulin-mediated glucose uptake in overweight/moderately-obese individuals. 148 healthy nondiabetic subjects with BMI 25-38 kg/m2 underwent subcutaneous adipose tissue biopsies. Cell-size distributions were obtained with Beckman Coulter Multisizer. Insulin sensitivity was quantified by steady-state plasma glucose (SSPG). Cell-size and metabolic parameters were compared by regression for the whole group;according to IR and IS subgroups;and by body fat quintile. Both large and small adipose cells were present in nearly equal proportions. Diameter of the large adipose cells was associated with %body fat (r=0.26, p=0.014), female sex (r=0.21,p=0.036), and SSPG (r=0.20,p=0.012). Percent small cells was associated only with SSPG (r=0.26, p=0.003). In the highest vs lowest % body fat quintile, despite a 50% difference in body fat, cell size increased by only 7% whereas cell number increased by 74%. IR individuals demonstrated a decreased proportion and number of large adipose cells but greater large cell diameter compared with body-fat matched IS individuals. Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m2. Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance. Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, while the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2-/- mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2-/-mice than in WT mice. In Lcn2-/- mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of PPARγprotein was significantly down-regulated, while the gene expression of extracellular matrix (ECM) proteins was up-regulated selectively in epididymal adipocytes of Lcn2-/- mice. Consistent with these observations, collagen deposition was selectively higher in epididymal, but not in inguinal adipose depot of Lcn2-/- mice. Administration of the PPARγagonist Rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did alter the responsiveness of adipose tissue to Rosi-effects on the ECM expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2-/- mice, which may be associated with a more pronounced effect of Rosi-treatment in reducing TGF-βin Lcn2-/- adipose tissue. Consistent with these in vivo observations, Lcn2 eficiency reduces the adipocyte differentiation capacity of stromal-vascular (SV) cells isolated from HFD-fed mice in these cells. Herein Rosi-treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2-/- inguinal and epididymal SV cells. Thus, combined our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling. Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese adolescents. Based on their 2-h glucose tests they were stratified in the following groups: group 1, 2-h glucose level <120 mg/dL;group 2, 2-h glucose level between 120 and 140 mg/dL;and group 3, 2-h glucose level >140 mg/dL. Liver and adipose tissue insulin sensitivity were greater in group 1 than in group 2 and group 3, and muscle insulin sensitivity progressively decreased from group 1 to group 3. The expression of the carbohydrate-responsive element-binding protein (ChREBP) was decreased in adipose tissue but increased in the liver (eight subjects) in adolescents with impaired glucose tolerance or type 2 diabetes. The expression of adipose ChREBPαand ChREBPβwas inversely related to 2-h glucose level and positively correlated to insulin sensitivity. Improvement of glucose tolerance in four subjects was associated with an increase of ChREBP/GLUT4 expression in the adipose tissue. In conclusion, early in the development of prediabetes/type 2 diabetes in youth, ChREBPβexpression in adipose tissue predicts insulin resistance and, therefore, might play a role in the regulation of glucose tolerance.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
McLaughlin, T; Lamendola, C; Coghlan, N et al. (2014) Subcutaneous adipose cell size and distribution: relationship to insulin resistance and body fat. Obesity (Silver Spring) 22:673-80
Guo, Hong; Bazuine, Merlijn; Jin, Daozhong et al. (2013) Evidence for the regulatory role of lipocalin 2 in high-fat diet-induced adipose tissue remodeling in male mice. Endocrinology 154:3525-38
Kursawe, Romy; Caprio, Sonia; Giannini, Cosimo et al. (2013) Decreased transcription of ChREBP-α/β isoforms in abdominal subcutaneous adipose tissue of obese adolescents with prediabetes or early type 2 diabetes: associations with insulin resistance and hyperglycemia. Diabetes 62:837-44
Yang, Jian; Eliasson, Bjorn; Smith, Ulf et al. (2012) The size of large adipose cells is a predictor of insulin resistance in first-degree relatives of type 2 diabetic patients. Obesity (Silver Spring) 20:932-8
MacKellar, Jennifer; Cushman, Samuel W; Periwal, Vipul (2010) Waves of adipose tissue growth in the genetically obese Zucker fatty rat. PLoS One 5:e8197
Santoro, Nicola; Kursawe, Romy; D'Adamo, Ebe et al. (2010) A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 52:1281-90
McLaughlin, Tracey M; Liu, T; Yee, Gail et al. (2010) Pioglitazone increases the proportion of small cells in human abdominal subcutaneous adipose tissue. Obesity (Silver Spring) 18:926-31
Kursawe, Romy; Eszlinger, Markus; Narayan, Deepak et al. (2010) Cellularity and adipogenic profile of the abdominal subcutaneous adipose tissue from obese adolescents: association with insulin resistance and hepatic steatosis. Diabetes 59:2288-96
Daigle Jr, Bernie J; Deng, Alicia; McLaughlin, Tracey et al. (2010) Using pre-existing microarray datasets to increase experimental power: application to insulin resistance. PLoS Comput Biol 6:e1000718
McLaughlin, T; Deng, A; Yee, G et al. (2010) Inflammation in subcutaneous adipose tissue: relationship to adipose cell size. Diabetologia 53:369-77

Showing the most recent 10 out of 14 publications