When The Brain Stops Listening: Leptin Resistance As A Driver Of Hippocampal Dysfunction And Cognitive Impairment"- A Systematic Review

Background:Leptin, a key adipocyte-derived hormone, is essential for maintaining energy homeostasis and also plays a significant neuromodulatory role, particularly within the hippocampus—a brain region critical for learning, memory, and executive function. In obesity and related metabolic disorders, persistent elevation of leptin levels often leads to leptin resistance, a condition marked by reduced sensitivity to leptin signalling. This resistance not only contributes to the progression of obesity but also adversely affects hippocampal function and cognitive performance. Scope of the Review:This review explores the mechanistic links between hippocampal leptin resistance and the impairment of synaptic plasticity. Special focus is given to its detrimental effects on long-term potentiation (LTP) and long-term depression (LTD), two cellular processes fundamental to memory consolidation and learning. Major Findings: Emerging evidence reveals that leptin resistance disrupts N-Methyl-D-aspartate (NMDA) receptor signalling and alters hippocampal architecture, resulting in impaired spatial memory and cognitive decline. High-fat diets (HFDs), a major contributor to leptin resistance, further compromise hippocampal synaptic function. Both animal and human studies underline the relevance of these mechanisms in the context of obesity-induced neurocognitive dysfunction. Conclusions and Future Directions: Therapeutic strategies aimed at restoring leptin signalling, such as the use of leptin sensitizers (e.g., amylin analogs, Celastrol), show promise in alleviating cognitive impairments. Additionally, lifestyle modifications like caloric restriction and regular physical activity can enhance leptin sensitivity and promote synaptic health. This review highlights the potential of targeted interventions in mitigating obesity-associated cognitive decline through restoration of hippocampal leptin signalling.