Fat pads dynamically regulate energy storage capacity under energy excess and deficit. This remodeling process is not completely understood, with controversies regarding differences between fat depots and plasticity of adipose cell number. We examined changes of mouse adipose cell-size distributions in epididymal, inguinal, retroperitoneal, and mesenteric fat under both weight gain and loss. With mathematical modeling, we specifically analyzed the recruitment, growth/shrinkage, and loss of adipose cells, including the size dependence of these processes. We found a qualitatively universal adipose tissue remodeling process in all four fat depots: (1) There is continuous recruitment of new cells under weight gain;(2) The growth and shrinkage of larger cells (diameter >50 m) is proportional to cell surface area;and (3) Cell loss occurs under prolonged weight gain, with larger cells more susceptible. The mathematical model gives a predictive integrative picture of adipose tissue remodeling in obesity. 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.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2012
Total Cost
$77,600
Indirect Cost
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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-?/? 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

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