LEPTIN RESISTANCE AND ITS ROLE IN THE PATHOPHYSIOLOGY OF OBESITY AND METABOLIC DISORDERS: A LITERATURE REVIEW
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5113Keywords:
Leptin Resistance; Obesity; Hypothalamus; Neuroinflammation; Endoplasmic Reticulum StressAbstract
Introduction: Obesity is a global health crisis linked to severe metabolic comorbidities. Leptin, a key hormone regulating energy homeostasis, fails to suppress appetite in obese individuals despite hyperleptinemia—a state known as leptin resistance.
Methods: This study presents current knowledge on leptin resistance and its role in obesity and metabolic disorders. A narrative literature review was conducted using PubMed, Scopus, and Web of Science, focusing on recent molecular studies, neuroendocrine mechanisms, and cardiometabolic consequences.
Key findings Leptin resistance involves a multi-level failure of the signaling axis, including impaired blood-brain barrier transport, LepRb receptor downregulation, and JAK2-STAT3 cascade disruption. Key molecular drivers include intracellular inhibitors (SOCS3, PTP1B), endoplasmic reticulum (ER) stress, and diet-induced hypothalamic neuroinflammation. This state leads to severe consequences, such as ectopic lipid accumulation, lipotoxicity, and peripheral insulin resistance.
Conclusion: Leptin resistance is a central pathogenic mechanism in obesity and metabolic syndrome. Targeting specific molecular blockades through novel leptin sensitizers and incretin-based polypharmacology represents a highly promising frontier for future anti-obesity therapies.
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Copyright (c) 2026 Karol Dąbek, Kamila Czyżak, Urszula Marzec, Aleksandra Cyrkler, Natalia Cieślak, Agata Chodkowska, Eliza Rajca, Agnieszka Giza, Paulina Giza, Karolina Wymoczył
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