Leptin: structure, function and biology.
Leptin is an adipocyte-derived hormone that acts as a major regulator for food intake and energy homeostasis. Leptin deficiency or resistance can result in profound obesity, diabetes, and infertility in humans. Since its discovery, our understanding of leptin's biological functions has expanded from anti-obesity to broad effects on reproduction, hematopoiesis, angiogenesis, blood pressure, bone mass, lymphoid organ homeostasis, and T lymphocyte systems. Leptin orchestrates complex biological effects through its receptors, expressed both centrally and peripherally. Leptin receptor belongs to the class I cytokine receptor superfamily. At least five isoforms of leptin receptor exist, primarily because of alternate splicing. The longest form is capable of full signal transduction. The short forms may serve as leptin binding proteins and play a role in leptin transporting across the blood-brain barrier. In this review, we present the crystal structure of leptin and the structural comparison with other four-helical cytokines, discuss the leptin-receptor binding models based on other cytokine-receptor complex structures, and summarize the most recent progress on leptin signal transduction pathways--especially its link to peripheral lipid metabolism through AMP-activated protein kinase and hepatic stearoyl-CoA desaturase-1 pathways. Furthermore, we propose the structure based design of leptin analogs with increased stability, improved potency, enhanced blood-brain barrier transport, and extended time action for future therapeutic application.
Zhang
Faming
F
Department of Chemistry, Indiana University at Bloomington, Bloomington, Indiana 47405, USA.
Chen
Yanyun
Y
Heiman
Mark
M
Dimarchi
Richard
R
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001692:Biological Transport; D003460:Crystallization; D004268:DNA-Binding Proteins / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D020738:Leptin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D012995:Solubility; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism
D000091162:AMP-Activated Protein Kinase Kinases; D004268:DNA-Binding Proteins; D020738:Leptin; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C515448:LEPR protein, human; C494086:STAT3 protein, human