Insulin resistance in obesity and type 2 diabetes (IRADIPOLAB)

Chronic activation of stress-responsive pathways by persistent nutrient overload contributes to the maladaptive responses involved in adipose tissue dysfunction and the development of insulin resistance. Therefore, stress-responsive proteins could be attractive targets against insulin resistance induced by obesity. We have shown that different stress-responsive proteins (p53, REDD1) are induced in adipocytes during obesity, in response to genotoxic stress or hypoxia, and mediate alterations in insulin signalling pathways and in their metabolic and secretory functions (Vergoni B et al, Diabetes 2016, Regazzetti C et al, PLoS One 2012). The objective of this project is to improve our knowledge of the connection between the activation of these stress-responsive proteins and adipose tissue dysfunction and insulin resistance. We are deciphering their mode of action and mechanisms of activation in adipocytes and adipose macrophages, and we are evaluating whether their inhibition can prevent obesity and insulin resistance.  

Our team made the original demonstration that the Rab GTPase Rab4, which is involved in endosomal trafficking, controls glucose transport in adipocytes through the regulation of the translocation of the glucose transporter Glut4 in response to insulin (Cormont et al, Mol Cell Biol 1996; Kaddai et al, PloS One 2009). More recently, we have shown that dysregulation of Rab4b-dependent endocytic trafficking in adipose T cells is a new mechanism involved in adipose tissue dysfunction and insulin resistance development (Gilleron et al, Cell Reports 2018). Also, it was demonstrated that Rab-dependent endocytosis controls liver metabolism (Gilleron J et al, Traffic 2019) and our recent data identify several proteins of the Rab family whose expression in liver is modified depending on the nutritional state. The objective of this project is to improve our knowledge of the role of Rab proteins and their regulators in the control of glucose and lipid metabolism and insulin sensitivity. We are currently exploring if and how Rab proteins tune the metabolism of glucose and lipids and the energetic metabolism in adipocytes, T cells, and hepatocytes. We are also elucidating the role of these novel potential metabolic regulators in the development of insulin resistance.

In obesity, the excess calory intake triggers an excessive development of fat mass by promoting hyperplasia and hypertrophy of white adipocytes. Conversely, the mass and activity of thermogenic adipocytes localized in white adipose tissue, called beige or brite adipocytes, is reduced. Stimulating beige adipocyte formation/activity protects against obesity and related metabolic disorders. The objective of this project is to identify new regulators of the beiging adaptation of the white adipose tissue. We are currently studying the central role of transcriptional coactivator in the genetic program controlled by sex hormones during beiging adaptation of white adipose tissue and the functional role of mechanosensitive ion channels in the differentiation and activity of the thermogenic beige adipocytes.