Structural studies on the extracellular assembly of the human leptin signalling complex.

The adipocyte-derived hormone leptin is crucial for regulating body weight and energy homeostasis. The primary target cells for leptin are neurons in the arcuate nucleus of the hypothalamus. Under normal physiological conditions leptin signaling acts as a molecular feedback mechanism that reduces appetite and stimulates energy expenditure. In conditions of leptin resistance, a decreased sensitivity to leptin signaling results in the inability to sense satiety which leads to the development of obesity. Despite decades of research on leptin and its receptor (LepR) as key regulators of body weight and homeostasis, the mechanism for the assembly of the leptin signaling complex is poorly understood at the molecular level. Building on recently acquired structural and mechanistic insights we produced a stabilized version of the extracellular assembly of the human leptin complex suitable for high-resolution cryoEM imaging.