Function
Leptin is a crucial regulator of energy balance and body weight control. Once released into the bloodstream, it exerts both central and peripheral effects by binding to the leptin receptor (LEPR) found in various tissues. This binding activates several major signaling pathways.
In the hypothalamus, leptin acts as an appetite-regulating factor. It decreases food intake and increases energy expenditure by inducing anorexigenic factors (suppressing appetite) and suppressing orexigenic neuropeptides (stimulating appetite). Additionally, it regulates bone mass and the secretion of hypothalamo-pituitary-adrenal hormones.
Peripherally, leptin increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, exhibits pro-angiogenic activity on endothelial cells, and modulates both innate and adaptive immunity.
Within the arcuate nucleus of the hypothalamus, leptin activates POMC neurons via depolarization, inducing the expression of FOS and SOCS3, leading to the release of anorexigenic peptides. Conversely, it inhibits NPY neurons via hyperpolarization, inducing SOCS3 expression and reducing the release of orexigenic peptides.
Beyond its well-established satiety-inducing effect, leptin also plays a modulatory role in nutrient absorption. In the intestine, it reduces glucose absorption by enterocytes by activating PKC, which sequentially activates p38, PI3K, and ERK signaling pathways, ultimately inhibiting glucose uptake.
Leptin acts as a growth factor in specific tissues. Through the activation of various signaling pathways, it increases the expression of genes involved in cell cycle regulation, such as CCND1 (via the JAK2-STAT3 pathway), and VEGFA (via the MAPK1/3 and PI3K-AKT1 pathways).
Leptin can also induce apoptosis via the JAK2-STAT3 pathway and upregulation of BIRC5 expression.
As a pro-angiogenic factor, leptin possesses mitogenic activity on vascular endothelial cells and participates in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).
In innate immunity, leptin modulates the activity and function of neutrophils by enhancing chemotaxis and the secretion of oxygen radicals. It increases phagocytosis by macrophages and promotes the secretion of pro-inflammatory mediators. Additionally, leptin enhances the cytotoxic ability of NK cells.
Leptin plays a pro-inflammatory role, acting synergistically with IL1B to induce NOS2, which promotes the production of IL6, IL8, and Prostaglandin E2 via a signaling pathway involving JAK2, PI3K, MAP2K1/MEK1, and MAPK14/p38.
In adaptive immunity, leptin promotes the differentiation of memory T-cells towards T helper-1 cell immune responses. It increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation through MTOR signaling pathway activation and BCL2 upregulation.