Figure1. Leptin signaling pathway.
Leptin (LP) is a protein hormone secreted by adipose tissue. It has been widely believed that after entering the blood circulation, it will participate in the regulation of sugar, fat and energy metabolism, prompting the body to reduce food intake, increase energy release, inhibit the synthesis of fat cells, and thus reduce weight. Halaas et al. applied DNA recombination technology in 1995, and the expression product of the ob gene is synthesized from E. coli, and the protein is named as levels of human plasma leptin are directly proportional to body fat weight, and leptin and its receptor gene mutations can lead to morbid obesity. The function of leptin is multifaceted, mainly in the regulation of fat and body weight: appetite suppression: leptin can significantly reduce human feeding, body weight, and body fat content. Increase energy consumption: Leptin can act on the center to increase sympathetic nerve activity and convert a large amount of stored energy into heat energy release; leptin can directly inhibit fat synthesis and promote its decomposition, and some people think that leptin can promote fat cell maturation. In addition, insulin can promote the secretion of leptin, which in turn plays a negative feedback regulation on the synthesis and secretion of insulin.
Leptin is a protein hormone secreted by fat cells and is mainly produced by white fat. Brown fat, skeletal muscle, bone mucosa, placenta and fetal heart, bone, and soft bone tissue can also secrete. It consists of three exons and two introns with a mRNA length of 4.5 kb and an open reading frame capable of encoding 167 amino acids. Isse et al. cloned the human leptin gene, which is located on chromosome 7, has a full length of 20 kb, consists of three exons and two introns, and the 5' end contains multiple transcription factor junctions, which is a single copy gene. In cattle, the leptin gene is located on chromosome 4, which is also composed of three exons and two introns. The coding region is located on the second and third exons, and the gene is about 18.9 kb in length. The full-length 2.93 kb leptin is a lipid-derived endocrine hormone encoded by the leptin gene. It consists of 167 amino acids. The N-terminus of the polypeptide contains a signal peptide of 21 amino acids. After processing, it contains 146 amino acid residues. The molecular weight is 16 kDa. Leptin proteins in animals between different species are highly conserved. Zhang et al. compared the amino acid sequences of cattle, humans, orangutans, rhesus monkeys, pigs and mice and found that the homology was 67%. The three-dimensional structure of leptin was studied. The final nuclear magnetic resonance analysis showed that leptin is a four-helix bundle cytokine composed of four antiparallel alpha helices. In addition, nuclear magnetic resonance and crystal structure analysis indicate that leptin also contains a disulfide bond that is critical for the function of leptin, as destruction of cysteine leads to loss of leptin biological activity. Studies in humans have also shown that inactivation of the leptin gene and the leptin receptor gene leads to abnormal secretion of leptin, which ultimately leads to excessive appetite and severe obesity.
Leptin signaling pathway
Leptin signaling pathway cascade
Leptin is known to regulate reproduction, bone homeostasis and immune signaling. Leptin is also implicated in various physiological processers such as angiogenesis and hematopoiesis. LEPRb forms a homodimer and binds to leptin in 1:1 stoichiometry. This tetrameric receptor/ ligand complex appears to be essential for signaling. Leptin receptor lacks intrinsic kinase activity. It mediates multiple signaling pathways by binding to cytoplasmic kinases such as Janus Kinase 2 (JAK2). Activation of JAK2 by leptin promotes the tyrosine phosphorylation of LEPRb at Tyr-986, Try-1078 and Tyr-1141, thus activating LEPRb. Activation of leptin receptor with leptin activates signaling modules such as JAK/STAT, RAS/RAF/MAPK, IRS1/PI-3K, PLCγ and AMPK/ACC modules. Tyrosine phosphorylation of LEPRb induces binding of STATs to LEPRb. Binding of STATs to the phosphorylated residues of LEPR leads to the JAK2 mediated tyrosine phosphorylation and activation of STATs. Activated STATs translocate to the nucleus and induces expression of genes such as suppressor of cytokine signaling 3 (SOCS3) and TIMP metallopeptidase inhibitor 1 (TIMP1). SOCS3 mediates feedback inhibition of leptin pathway by binding to Tyr-986 residue of LEPR.
The secretion of leptin has a circadian rhythm, which is characterized by high evening, low morning, and impulsive secretion. The peak appears at 22: 00-3: 00 (median 1:20), and the trough appears at 8:00-17:40 (median around 10:30). However, the frequency, amplitude and circadian rhythm of pulsatile release are related to gender, obesity and insulin concentration. Hunger and cold can inhibit the secretion of leptin, which may be a protective response of the body in harsh environments. Growth hormone, changes in diet, and sleep can also affect the secretion of leptin.
Relationship with disease
Leptin and its receptor play an important role in the process of glucose metabolism. Leptin can enhance the sensitivity of insulin and glucose uptake in surrounding tissues. Leptin is a negative regulator of insulin and participates in insulin resistance.
Type I diabetes
Leptin is an important regulator of carbohydrate metabolism. Type 1 diabetes is mainly insulin-dependent diabetes. The islet cell function is obviously degraded or even lost in the early stage. The absolute deficiency of insulin is common in children and adolescents. The onset is rapid and must rely on subcutaneous injection of insulin and hypoglycemic therapy. Leptin helps reverse high glucose status or can increase insulin sensitivity by indirect hypoglycemic, binding to the liver leptin receptor to regulate hepatic glucose metabolism.
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