Leptin Signaling in Neurocognitive Disorders
Summary
Leptin, a hormone predominantly secreted by adipose tissue, exerts far-reaching roles in the central nervous system beyond its established function in energy homeostasis. In the brain, leptin modulates neuronal excitability, synaptic plasticity and neurogenesis through signalling cascades such as JAK-STAT, PI3K-Akt and MAPK. These pathways confer neuroprotective effects by stabilising mitochondrial function, reducing oxidative stress and attenuating excitotoxic injury. In neurocognitive disorders including Alzheimer’s disease and Parkinson’s disease, alterations in leptin transport across the blood–brain barrier and changes in receptor expression or downstream signalling contribute to a state of central leptin resistance. This resistance is exacerbated by peripheral inflammation and metabolic dysfunction commonly associated with obesity, thereby linking adiposity to heightened risk of cognitive decline. Pathological hallmarks such as amyloid-β accumulation and the presence of APOE4 alleles further impair leptin signalling, promoting synaptic loss and glial activation. Understanding these interconnections has opened avenues for therapeutic approaches aimed at restoring leptin sensitivity or mimicking its neurotrophic actions to slow or prevent cognitive deterioration.
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Leptin Signaling in Neurocognitive Disorders publication trend
The graph below shows the total number of articles in leptin signaling in neurocognitive disorders across all publications each year (not limited to Nature Index journals).
Technical terms
Leptin: A peptide hormone produced by fat cells that regulates appetite, metabolism and a range of neural functions.
Leptin resistance: A condition in which reduced sensitivity to leptin in the brain impairs its signalling, often linked to obesity and inflammation.
Blood–brain barrier (BBB): A selective vascular interface that regulates the passage of molecules between the bloodstream and the central nervous system.
JAK-STAT pathway: A signalling cascade activated by cytokine and hormone receptors that regulates gene expression involved in cell survival and proliferation.
PI3K-Akt pathway: An intracellular signalling route that promotes neuronal growth, metabolic regulation and resistance to apoptotic stimuli.
References
- Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies. International Journal of Molecular Sciences (2023).
- Impact of serum leptin and adiponectin levels on brain infarcts in patients with mild cognitive impairment and Alzheimer’s disease: a longitudinal analysis. Frontiers in Endocrinology (2024).
- Leptin-mediated Cell Survival Signaling in Hippocampal Neurons Mediated by JAK STAT3 and Mitochondrial Stabilization*. Journal of Biological Chemistry (2007).
- Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro *. Journal of Biological Chemistry (2008).
- Leptin promotes rapid dynamic changes in hippocampal dendritic morphology. Molecular and Cellular Neuroscience (2007).
- Leptin regulation of neuronal excitability and cognitive function. Current Opinion in Pharmacology (2007).
- Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease. Aging Cell (2014).
- Obesity as a Risk Factor for Dementia and Alzheimer’s Disease: The Role of Leptin. International Journal of Molecular Sciences (2022).
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