(Press-News.org)
The World Health Organization describes obesity as an epidemic that disrupts metabolic equilibrium, characterized by an excess of adipose tissue and chronic inflammation. This state arises from various factors, including genetic predispositions and lifestyle choices like high caloric intake and physical inactivity. Leptin, primarily produced by adipose tissue, regulates hunger by signaling satiety to the hypothalamus. However, in obesity, leptin's transport to the brain is often blocked, leading to leptin resistance. This resistance complicates leptin’s utility as a therapeutic agent due to dysfunctional signaling pathways that emerge in brain regions critical for appetite regulation and energy homeostasis.
Methods
This review is part of the "Project ATA," a large, multicenter study using bioinformatics tools to systematically analyze leptin signaling pathways. The research utilizes high-level data from sources like UniProt and Gene Ontology, combined with experimental findings, to pinpoint molecules involved in leptin and insulin interaction pathways. Systematic literature searches were performed across PubMed, ScienceDirect, and Google Scholar using terms such as "leptin," "insulin resistance," and "obesity," ensuring that the curated data met reproducibility standards.
Obesity, Leptin Resistance, and Metabolic Syndrome
MS, defined by a constellation of high blood pressure, elevated triglycerides, insulin resistance, and abdominal obesity, is a major risk factor for cardiovascular and metabolic diseases. The review highlights how obesity-driven elevations in leptin levels—commonly known as hyperleptinemia—exacerbate metabolic syndrome. Elevated leptin levels trigger insulin resistance by activating pro-inflammatory pathways that induce mitochondrial dysfunction and oxidative stress, both implicated in T2DM. Moreover, hyperleptinemia leads to further leptin resistance, creating a feedback loop that worsens obesity and metabolic outcomes.
Molecular Mechanisms of Leptin Resistance
Leptin resistance involves various molecular alterations, particularly in leptin transport and receptor function. Key proteins, such as suppressor of cytokine signaling (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B), inhibit leptin receptor signaling by promoting the degradation of receptor-associated proteins and blocking downstream signaling cascades. Additionally, chronic endoplasmic reticulum (ER) stress and inflammation from high-fat diets further disrupt leptin signaling within proopiomelanocortin (POMC) neurons. This stress inhibits the JAK/STAT pathway, which is essential for leptin's satiety effects and contributes to persistent leptin resistance.
Leptin and Insulin Resistance Pathway Convergence
At the cellular level, leptin signaling intersects with insulin pathways in pancreatic β-cells. When leptin binds to its receptors in these cells, it modulates insulin secretion by influencing pathways like phosphoinositide 3-kinase (PI3K) and the cyclic AMP (cAMP) pathway. Under leptin resistance, these pathways become dysregulated, promoting hyperinsulinemia. The FoxO1 transcription factor, which is influenced by leptin, also directly impacts insulin gene expression; when dysregulated, it further impairs insulin release and signaling, contributing to glucose imbalance and the onset of T2DM. Furthermore, the overactivation of pathways involving Rho GTPase Cdc42 and MAP kinases like ERK exacerbates insulin resistance by increasing oxidative stress and promoting inflammation.
Future Directions
Continued research is needed to validate these pathways experimentally and develop interventions that precisely target leptin signaling dysregulation. Such efforts could pave the way for novel therapies capable of addressing the underlying metabolic disturbances in obesity, potentially alleviating the global burden of metabolic syndrome and related diseases.
Conclusions
This review underscores the intricate molecular interplay between leptin resistance, obesity, and metabolic syndrome, revealing pathways that offer potential targets for therapeutic intervention. The failure of exogenous leptin treatments in obesity suggests the need for alternative approaches, such as targeting downstream molecules within leptin signaling pathways. Bioinformatics insights guide future research toward therapeutic strategies aimed at restoring leptin sensitivity or mitigating its metabolic effects, such as the use of glucagon-like peptide-1 receptor agonists.
Full text
https://www.xiahepublishing.com/1555-3884/GE-2024-00039
The study was recently published in the Gene Expression.
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