Endospanins, new regulators of leptin receptor : impact on obesity and diabetes – ENDOLEPR

Obesity is a major public health problem associated with the development of type 2 diabetes (T2D). Leptin targets specific receptors (OB-R) expressed in the hypothalamus to regulate energy balance and glucose homeostasis. Leptin induces decrease of food intake and increase of energy expenditure in normal people but does not function in obese people, indicative of a leptin resistance state. We characterized a new family of OB-R regulators, the endospanin family composed of endospanin 1 and 2 which are ubiquitously expressed. These proteins interact with OB-R and retain OB-R inside the cell limiting the number of OB-R at the cell surface, which can be activated by leptin. Hence, increasing OB-R at the cell surface has been shown to ameliorate leptin sensitivity of the cell. In line with this, endospanin 1 silencing precisely in the hypothalamic Arcuate Nucleus of mouse brain prevents and reverses high fat diet-induced obesity in mice by increasing leptin-induced STAT3 activation. Interestingly, endospanin 1 silencing has differential effects on OB-R signaling pathways: while it increases STAT3 activation it abrogates PI3K/AKT activation indicative of a differential role of endospanin 1 on OB-R function. Moreover, very little is known on the role of endospanin 2 and its effect on OB-R functions.
We therefore aim to study i) the differential effect of endospanin 1 and 2 on OB-R signaling, ii) the impact of endospanin 1 general or brain specific knock-out in transgenic mice, and iii) investigate small-molecule compounds, resulting from a High Throughput Screening, and able to increase cell OB-R surface expression and concomitantly signaling. Research on this field would advance the understanding of the function of a receptor important in the field of obesity and help the elaboration of therapeutic tools against obesity and T2D.