MAMA

Proposal context: Obesity prevalence is tightly associated with cardiometabolic morbidity. Growing evidence supports that adipocyte dysfunction is central in the development of obesity-related metabolic complications. Therefore, a better understanding of the molecular mechanisms sustaining adipocyte dysfunction will open new therapeutic perspectives to manage the complications of obesity. Seipin is an endoplasmic reticulum (ER) transmembrane protein highly expressed in WAT, encoded by the gene BSCL2. In human, BSCL2 mutation is the cause of the Berardinelli-Seip generalized lipodystrophy (BSCL), characterised by a lack of WAT and severe metabolic complications (i.e. insulin resistance, diabetes, liver steatosis). There are evidences showing that seipin controls adipocyte “good health” but its biological function in mature adipocytes remains to be investigated. Using cellular and mice models, we have revealed that seipin is localized at the mitochondria associated membrane (MAMs). MAMs allow exchanges of phospholipids and calcium (Ca2+) between ER and mitochondria. In the liver and the muscle, we have demonstrated that MAMs are crucial hubs for hormone and nutrient signalling regulating insulin sensitivity and metabolic flexibility. However, the importance of MAMs in white adipose tissue (WAT) has not been sufficiently studied. Scientific aims of the proposal: Starting from the investigation on Seipin function in MAMs, MAMA will explore the importance of MAMs in WAT homeostasis and metabolic flexibility, and their potential dysfunction in obesity and Type 2 diabetes (T2D). Our preliminary demonstrated that: 1) In mice, seipin deficiency leads to adipocytes loss 2) Seipin recruitment at MAMs is promoted by fasting; 3) Seipin deficiency alters ER to mitochondria Ca2+ import; 4) Seipin deficiency alters mitochondrial lipid composition; 5) Beyond Seipin, MAMs number is nutritionally regulated in adipocytes. The proposal contains 3 work-packages WP1: To unravel the function of Seipin in MAMs in mature adipocytes. WP1 will allow us to define the sub-cellular localization of seipin under different nutritional status and the effect of seipin deficiency on MAMs properties. We will decipher the role of seipin in lipid homeostasis and in ER to mitochondria Ca2+ flux. We will address the effects of seipin deficiency on mitochondrial properties and the role of seipin in metabolic flexibility. Finally, we will be able to state if these effects of seipin deficiency are MAMs dependent. WP2: To highlight the role of MAMs in adipocyte metabolic flexibility. WP2 will reveal, both in vitro and in vivo, the effects of the nutritional status on MAMs number and properties in adipocytes and the effect of MAMs modulation on adipocyte properties. WP3: To characterize WAT MAMs in obesity and T2D. WP3 will allow us to describe for the first time the changes in MAMs number and properties in the adipose tissue of T2D mice and human patients. We will be able to correlate these changes with systemic insulin sensitivity. Finally, we will test if adipocyte MAMs modulation can by itself correct the cardiometabolic complications associated with obesity and T2D. Novelty and importance: In this project, using unique biological tools and multiple approaches, from animal physiology to cell biology and biophysics, we are proposing to study the physiological importance of MAMs in determining adipocyte homeostasis. If modulating MAMs in obese adipose tissue proves able to counteract the deleterious metabolic complications associated with obesity, this could lead to the identification of new promising therapeutic targets.