Cellular and Molecular Pathophysiology of Obesity and Diabetes

The team investigates the complex mechanisms involved in the pathophysiology of the insulin resistance associated with obesity and type 2 diabetes, with a special focus on the molecular and cellular mechanisms connecting the pathological expansion and dysfunction of adipose tissue to the development of insulin resistance in obese and type 2 diabetic patients.

Research Focus

Despite the wealth of research, the progress in the clinical management of insulin resistance of obese and type 2 diabetic patients has been poor. Pathological expansion and dysfunction of white adipose tissue in obese individuals is an important trigger of insulin resistance. White adipose tissue dysfunction is characterized by the development of cellular stress in adipocytes and in the stroma of the adipose tissue such as hypoxia, oxidative and endoplasmic reticulum stress and by a low grade inflammatory state due to infiltration of inflammatory immune cells and increased production of inflammatory cytokines. Targeting dysfunctional white adipose tissue and/or improving its “healthy” expansion appear as a potential therapeutic avenue against insulin resistance and to lower the risk to develop Type 2 diabetes.

In this context, the overarching objectives of the team is 1) to identify key molecular actors induced by adipose cellular and inflammatory stress and to decipher their mechanistic role in the metabolic and endocrine dysfunction of adipose tissue and the development of the insulin resistance and 2) to examine the molecular mechanisms by which hormones, especially sexual hormones, control white adipose tissue expansion and function, the conversion of white to beige adipocytes, the regulation of energy balance and the insulin sensitivity.

Main achievements

Over the past ten years, we have identified in adipocytes or in adipose immune cells novel stress pathways (DNA damage and p53 pathway, hypoxia and hypoxia-induced protein REDD1, Tpl2/ERK pathway) and novel cellular mechanisms (defect in endocytic processes controlled by the GTPase Rab4b) involved in adipose tissue inflammation/dysfunction and in insulin resistance.

1) The invalidation of the small GTPase Rab4b in T cells alters T cell populations in adipose tissue and causes adipose tissue dysfunction and insulin resistance (Gilleron J et al, Cell Report, in revision)

2) The REDD1 protein is involved in the inflammatory response of macrophages (Pastor F et al, Scientific Report, 2017)

3) DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes leading to adipose tissue inflammation, adipocyte dysfunction and insulin resistance (Vergoni B, Cornejo PJ et al, Diabetes, 2016)

4) The inflammatory MAP3 kinase Tpl2 and the MAP kinase ERK1 contribute to the cross-talk between adipocytes and macrophages leading to adipose tissue inflammation (Jager J et al, Diabetes, 2010; Jager J et al, Diabetologia, 2011; Ceppo F et al, Endocrinology, 2014; Berthou F, Ceppo F et al, Mol Endocrinol, 2015).

5) Hypoxia alters insulin signaling and action in adipocytes (Regazzetti C et al, Diabetes, 2009) through downregulation of cavin-1 and cavin-2 expression resulting in the disappearance of caveolae (Regazzetti C, Dumas K et al, Endocrinology, 2015).

6) Deciphering the endocytic trafficking steps regulated by the small GTPase Rab4b (Perrin L et al, J Cell Sci, 2013)

7) Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression (Jager J et al, Endocrinology, 2007)

Team Publications