Leptin signaling and leptin resistance

Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight.Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity.Leptin controls energy balance and body weight mainly through leptin receptor b(LEPRb)-expressing neurons in the brain,particularly in the hypothalamus.These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus,forming a neural network that controls the energy homeostasis and body weight.Multiple factors,including inflammation and endoplasmic reticulum(ER)stress,contribute to leptin resistance.Leptin resistance is the key risk factor for obesity.This review is focused on recent advance about leptin action,leptin signaling,and leptin resistance.

Role of Leptin in Immunity

Leptin, a protein hormone produced by the adipocytes, has long been recognized to regulate metabolism, neuroendorine and other physiological functions. Early findings of increased leptin production during infection and inflammation and dysregulated immune response in leptin signaling-deficient mice provide strong evidence for the involvement of leptin in the immune responses. Recent data have established the regulatory function for leptin in immunity similar to the function of a pro-inflammatory cytokine, while gene-targeting studies also demonstrated an essential role of leptin in regulating hematopoiesis and lymphopoiesis. Moreover, there has been increasing evidence that leptin is involved in the pathogenesis of various autoimmune diseases. This review discusses recent advances in understanding the role of leptin in immunity and leptin-signaling pathways involved in modulating immune homeostasis and autoimmune pathogenesis. Cellular ＆ Molecular Immunology. 2007;4（1）：1-13.

Leptin in normal physiology and leptin resistance

Since the discovery of leptin as an adipokine in1994, much progress has been made in the research about leptin. Circulating leptin binds to leptin receptor, activates STAT3-dependent and STAT3-independent signaling pathways, and plays an effective role in energy homeostasis, neuroendocrine function and metabolism mainly through acting on the central nervous system, especially the hypothalamus. Leptin resistance is considered as a key risk factor for obesity. Various mechanisms have been formulated in order to explain leptin resistance, including impairment in leptin transport, attenuation in leptin signaling, ER stress, inflammation and deficiency in autophagy. Here, we review our current knowledge about leptin action, leptin signaling and leptin resistance, hoping to provide new ideas for the battle against obesity.

Structural plasticity of human leptin binding to its receptor LepR

Leptin receptor(LepR)signaling plays an essential role in balancing food intake and energy expenditure.The architec-ture of LepR signaling assembly is critical for its function.In this study,we determined the structures of three distinct conformations of human leptin–LepR using cryo-electron microscopy at resolutions of 3.88,3.77,and 3.58Å.Both 2:2 and 3:3 stoichiometric assemblies were observed,and the complexes exhibited asymmetric open conformations.Lep-tin undergoes substantial rearrangement of its flexible regions to accommodate binding to LepR.The assembled leptin–LepR complexes connect through a“hand-in-hand”geometry.The open,interlocked 3:3 trimeric assembly results from the engagement of a third leptin–LepR heterodimer with a 2:2 dimer.The asymmetric geometry of LepR is substantially distinct from that of other gp130 cytokine homologs,and that may be due to the twisted and rigid interface between the D3 and D4 domains.These results highlight the distinct engagement of leptin with LepR and provide important insights into the structural plasticity of LepR-signaling assemblies.