Adipocytes were thought to be only the body's energy storage warehouse or filler between tissues and organs. Until 1994, the discovery of leptin broke the inherent understanding of adipose cells. Subsequently, other important functions of fat cells were gradually discovered. And humans recognize that fat cells are also an endocrine organ that secretes cytokines or hormones such as leptin, adiponectin, resistin, retinoid, visfatin, etc. The cytokines or hormones secreted by adipose cells are called adipocytokines (adipokines).
The adipocytokine signaling pathway refers to a series of cascade events involving the involvement of adipocytokines in the body.
Adipocytokines play an important role in obesity, insulin resistance, and the pathogenesis of type II diabetes by acting on target organs through autocrine or paracrine effect and blood circulation.
Leptin is a peptide hormone mainly produced and secreted by white adipocytes. And it is also expressed on the heart muscle, skeletal muscle, gastric mucosa, placenta, and lung, etc. Leptin exerts a wide range of biological functions by mediating many signal transduction pathways. Leptin receptors (LEPRs) are leptin specific receptors. Among six LEPR isoforms, LEPRb is the longest one and is responsible for leptin signaling.
Leptin binds to the LEPRb, leading to dimerization of the latter. Due to lack for the tyrosine kinase activity, LEPRb binds to cytoplasmic kinase Janus Kinase 2 (JAK2) to form the LEPRb/JAK2 complex. Activated JAK2 phosphorylates and then actives LEPRb, inducing the activation of many signaling molecules such as JAK/STAT (signal transducer and activator of transcription) and RAS/RAF/MAPK. The phosphorylated residues of the LEPRb serve as binding sites for STATs. LEPRb recruits STATs such as STAT3 ＆ STAT5 and phosphorylates them. Active STAT3 and STAT5 dissociate from the receptor to form dimers, which subsequently enter the nucleus and regulate specific gene transcription and protein synthesis. The JAK2/STAT3 signaling mediated by leptin plays an important role in energy homeostasis and neuroendocrine function. Suppressor of cytokine signaling 3 (SOCS3) works as a feedback inhibitor of leptin signaling. Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates JAK2, blocking leptin signaling.
Phosphorylated LEPRb also provides a binding site for SH2-containing protein tyrosine phosphatase 2 (SHP2). SHP2 is phosphorylated and binds to its effector molecule Grb2 (growth factor receptor-bound protein 2), activating the upstream signaling molecule MEK1. Activation of MEK1 phosphorylates and activates ERK1/2, ultimately leading to enhanced expression of specific target genes.
Leptin is also involved in the PI3K/Akt signaling pathway by phosphorylating insulin receptor substrate (IRS). Activated PI3K further activates protein kinase B (AKT1), mammalian target of rapamycin (mTOR), and PDE3A. Leptin also modulates 5'-AMP-activated protein kinase (AMPK) signaling.
Leptin regulates feeding and metabolism through 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the brain and peripheral organs.
Resistin belongs to the family of resistin-like molecules (RELMs) and is mainly expressed in white fat. Resistin has the effect of inhibiting insulin signaling and resisting insulin.
It has been found that in the lipid-defense cell 3T3-L1, resistin impairs the signaling system of insulin through an upregulation mechanism of inhibitory factors of the insulin cascade signal, especially SOCS-3. SREBP 1c acts as a transcription factor, which up-regulates the transcription of the resistin gene. Conversely, resistin can up-regulate the expression of SREIP-1c gene. Over-expressed resistin inhibits the uptake of insulin-stimulated glucose and the expression of PPAR ＆ IRS-2. But over-expressed resistin stimulates the expression of glucose 6 phosphatase, SREBP-1c, and SOCS-3. Increased expression of SRERP-1c can repress IRS-2 transcription, blocking the insulin signaling pathway. The inhibition of PPAR ＆ IRS-2 and the up-regulation of SOCS-3 by resistin impair the normal signaling pathway of insulin, leading to insulin resistance.
Adiponectin is a cytokine specifically secreted by adipocytes and has effects of enhancing insulin sensitivity, anti-hyperglycemia, and anti-atherosclerosis.
Adiponectin activates cAMP-activated protein kinase (AMPK) in skeletal muscle cells, catalyzing the phosphorylation of acetyl-CoA carboxylase. Phosphorylated AMPK inhibits acetyl-CoA degradation, enhancing intracellular fatty acids. On the other hand, AMPK activates mitogen-activated protein kinase p38, which enhances the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα), increasing the expression of fatty acid oxidation-related genes and promoting fatty acid oxidation. Adiponectin also activates the serine/threonine-protein kinase in hepatocytes, phosphorylating and deactivating of cAMP response element-binding protein coactivator 2 (CRTC2). Inactive CRTC2 inhibits the expression of gluconeogenesis related enzyme genes and the output of liver glycogen. An intracellular adaptor protein (APPLI) with a PH domain, a PTB domain, and a leucine zipper motif, can enhance adiponectin action and increase the transfer of glucose transporter 4 to the cell membrane ＆ glucose into cells by binding to an adiponectin receptor.
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