White Adipose Tissue Resilience to Insulin Deprivation and Replacement

Citation: Hadji L, Berger E, Soula H, Vidal H, Geloen A ( White Adipose Tissue Resilience to Insulin Deprivation and Replacement Lilas Hadji 0 Emmanuelle Berger 0 He di Soula 0 Hubert Vidal 0 Alain Ge loe n 0 Joseph Najbauer, University of Pecs Medical School, Hungary 0 1 Universite de Lyon, CARMEN INSERM U1060, INSA-Lyon , F-69621, Villeurbanne , France , 2 IXXI Complex Systems Institute , F-69007, Lyon, France, 3 EPI BEAGLE INRIA F- 69621, Villeurbanne , France Introduction: Adipocyte size and body fat distribution are strongly linked to the metabolic complications of obesity. The aim of the present study was to test the plasticity of white adipose tissue in response to insulin deprivation and replacement. We have characterized the changes of adipose cell size repartition and gene expressions in type 1 diabetes Sprague-Dawley rats and type 1 diabetic supplemented with insulin. Methods: Using streptozotocin (STZ)-induced diabetes, we induced rapid changes in rat adipose tissue weights to study the changes in the distribution of adipose cell sizes in retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous adipose tissues (scWAT). Adipose tissue weights of type 1 diabetic rats were then rapidly restored by insulin supplementation. Cell size distributions were analyzed using multisizer IV (Beckman Coulter). Cell size changes were correlated to transcriptional regulation of genes coding for proteins involved in lipid and glucose metabolisms and adipocytokines. Results: The initial body weight of the rats was 46565.2 g. Insulin privation was stopped when rats lost 100 g which induced reductions in fat mass of 68% for rWAT, 42% for eWAT and 59% for scWAT corresponding to decreased mode cell diameters by 31.1%, 20%, 25.3%, respectively. The most affected size distribution by insulin deprivation was observed in rWAT. The bimodal distribution of adipose cell sizes disappeared in response to insulin deprivation in rWAT and scWAT. The most important observation is that cell size distribution returned close to control values in response to insulin treatment. mRNAs coding for adiponectin, leptin and apelin were more stimulated in scWAT compared to other depots in diabetic plus insulin group. Conclusion: Fat depots have specific responses to insulin deprivation and supplementation. The results show that insulin is a major determinant of bimodal cell repartition in adipose tissues. - Changes in adipose mass throughout life are a common phenomenon in most individuals. Nevertheless nowadays the prevalence of individuals with an excessive accumulation of adipose tissue (obesity) has reached epidemic proportions. The main problem is that obesity is associated with metabolic disorders including insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular diseases and cancers, resulting in a decreased lifespan [1]. White adipose tissue is recognized as a dynamic endocrine organ able to produce and release numerous bioactive polypeptides known as adipokines. Obesity is defined as an excessive growth of adipose tissue resulting from increased number and size of adipose cells. As such, it is likely that adipokines could play an important role in the development of diseases related to obesity [2]. Furthermore, it is now well known that distribution of body fat plays a critical role in the metabolic complications related to obesity [3,4]. Besides the importance of body fat distribution, evidence increasingly shows a significant role of adipose cell size [5,6]. Adipose tissue of obese animals and humans is infiltrated by macrophage population. That infiltration is correlated to adipocyte size [7]. Numerous studies have described a bimodal cell size distribution in adipose tissue [8,9,10] allowing to classify adipocytes into small (below the nadir) and large sizes. These studies suggested that metabolic properties, such as insulin sensitivity and secretion of adipokines, depend on cell size distribution rather than mean cell size. Although such studies suggest that the development of metabolic deseases is conditionned not only by the quantity but also by the quality of adipose tissue (i.e. cellularity), very little is known about the dynamic of changes of adipose tissue cellularity. Differences in adipose cell size contribute to the health risks of obesity through altered production of hormones such as adiponectin and leptin [11]. Adipocyte size is an important determinant of adipokine secretion [5,12,13]. Indeed, enlarged adipocytes are associated with metabolic abnormalities such hyperinsulinemia, glucose intolerance, dyslipidemia [14]. Skurk et al. [15] observed a differential expression of pro- and anti-inflammatory factors with increased adipocyte size resulting in a shift toward dominance of pro-inflammatory adipokines largely as a result of a dysregulation of very large cells. More recent results showed an association between small adipose cells and inflammation [16]. Although it is assumed that insulin is a posi (...truncated)