Leptin

Leptin belongs to the family of long-chain helical cytokines (Matarese G 2000). Leptin is expressed by adipose tissue, gastric epithelium and brain cells (Bado A et al. 1998). In the hypothalamus, leptin stimulates the metabolic rate and inhibits appetite. Leptin has regulatory functions in angiogenesis, homeostasis, hematopoiesis, thermogenesis and chondrogenesis. Leptin also influences neuroendocrine and immunological processes (Fantuzzi G et al. 2000). For example, leptin acts as a pro-inflammatory cytokine in monocytes and lymphocytes, thereby promoting the production of Th1-type cytokines.
Leptin also influences reproductive processes. The maternal leptin concentration increases during pregnancy and decreases again after birth. Leptin influences the course of pregnancy by regulating the function and maturation of the ovaries and the development of the embryo (Cervero A et al. 2004). Leptin also promotes the proliferation of trophoblasts, fetal growth and lactation, and has an anti-apoptotic effect in osteoblasts, monocytes, eosinophil granulocytes and other cells (Conus S et al. 2005).

Leptin is a ligand of the leptin receptor (ObR, LEPR). The leptin receptor belongs to the gp130 family of cytokine receptors (Tartaglia LA et al. 1995). The leptin receptor is associated with tyrosine kinases via its cytosolic domain. It has no tyrosine kinase activity of its own. Alternative splicing results in the 6 leptin receptor isoforms: ObRa, ObRb, ObRc, ObRd, ObRe and ObRf (Harvey J et al. 2003).

Leptin itself is a target gene of the nuclear receptor PPARγ and thus also a target gene of RXRα, the heterodimeric partner of PPARγ. RXRα and PPARγ are probably also involved in the regulation of leptin in the placenta. RXR agonists are able to regulate leptin expression and thus positively influence the course of pregnancy. Leptin also influences reproductive processes. The maternal leptin concentration increases during pregnancy and decreases again after birth. Leptin influences the course of pregnancy by regulating the function and maturation of the ovaries and the development of the embryo (Cervero A et al. 2004).

Leptin also promotes the proliferation of trophoblasts, fetal growth and lactation, and has an anti-apoptotic effect in osteoblasts, monocytes, eosinophil granulocytes and other cells (Conus S et al. 2005).

Leptin and psoriasis:

Leptin is a hormone produced by the WAT that regulates appetite and energy balance. Its level is related to fat reserves and is involved in inflammatory diseases such as psoriasis. Elevated leptin levels are frequently observed in the plasma and skin of patients with psoriasis, especially in severe cases, and these levels are related to the severity of the disease as indicated by the PASI (Słuczanowska-Głabowska S et al. 2023; Wang R et al. 2024)

The main contribution of leptin to psoriasis lies in its ability to increase inflammation by stimulating the production of proinflammatory cytokines such as IL-1, IL-6, CXCL8 and TNF-α, which play a central role in the development of the inflammatory response (19,43). This cascade promotes a Th1/Th17 immune response that leads to elevated IL-17 and IL-23 levels, which exacerbate the characteristic symptoms of the disease (Su X et al. 2020; Su X et al. 2021).

Leptin also modulates immune cell function by promoting the differentiation of Th17 cells. This effect is mediated by the upregulation of the retinoic acid receptor-related orphan receptor γ t, an important transcription factor involved in the development of Th17 cells and thus contributing to the accumulation of IL-17 (Yu Y et al. 2013). In addition, leptin reduces the number and functionality of Tregs, decreases their production of IL-10 and further exacerbates inflammation (Walendzik K et al. 2020). Anti-leptin monoclonal antibodies have been shown to enhance Treg proliferation, while leptin receptor antagonists can increase Foxp3 expression and inhibit IL-17 production, highlighting the role of leptin in immune regulation. In addition, leptin activates the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, which amplifies the inflammatory response and promotes angiogenesis in psoriatic lesions, supporting ongoing inflammation and disease progression (Calautti E et al. 2018).

In keratinocytes, leptin influences proliferation and function by stimulating the release of amphiregulin, a growth factor that accelerates keratinocyte proliferation and contributes to the hyperproliferation observed in psoriatic lesions (51). In addition, leptin upregulates the expression of chemokines such as CXCL8, CXCL1 and CCL20, further stimulating keratinocyte proliferation and inflammation. It acts synergistically with IL-17A to enhance the expression of these chemokines and hBD2 via mitogen-activated protein kinases (MAPK) and JAK2 signaling pathways, leading to impaired keratinocyte maturation and excessive expression of disease-related genes (Kanda N et al. 2008).

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