Numerous studies have demonstrated a close relationship between leptin and type 2 diabetes mellitus (T2DM). For example, leptin levels are often elevated in T2DM patients and positively correlate with insulin resistance. In cases of obesity and T2DM, leptin resistance indicates that despite high leptin levels, its effects on appetite regulation and metabolism are markedly diminished. This leptin resistance may stem from dysregulation of leptin receptor signaling pathways or decreased leptin sensitivity, leading to reduced insulin sensitivity. High leptin levels may further exacerbate insulin resistance, accelerating T2DM progression. Additionally, certain polymorphisms in the leptin gene are associated with T2DM development; specific leptin gene variants have been linked to increased insulin resistance and T2DM susceptibility. These gene variations may alter leptin synthesis, secretion, or signaling, thereby increasing the risk of T2DM by modifying leptin signaling responsiveness.
Leptin is also notably associated with cardiovascular and metabolic complications in T2DM. Research indicates that elevated leptin levels in T2DM patients are significantly correlated with cardiovascular risk, particularly with asymptomatic myocardial infarction and carotid atherosclerosis. Increases in carotid intima-media thickness (cIMT) and atherosclerosis closely relate to elevated leptin levels. The underlying mechanisms are complex and involve known pathways such as promoting vascular endothelial inflammation, inducing oxidative stress, damaging the endothelium, accelerating atherosclerosis, and altering myocardial structure and function, thereby increasing cardiovascular disease risk.
Building on this foundation, researchers have developed various leptin-based therapeutic strategies for T2DM. In lipodystrophic patients, leptin replacement therapy improves insulin resistance in muscle and liver, suppresses hepatic gluconeogenesis and lipolysis, and lowers fasting hyperglycemia. This therapy suggests that maintaining normal leptin levels may help restore insulin sensitivity and improve metabolic status. Additionally, various antidiabetic drugs indirectly improve T2DM symptoms by modulating leptin levels or signaling pathways. For instance, metformin can lower leptin levels in T2DM patients, while studies in animal models have shown it enhances hepatic leptin receptor expression and improves hypothalamic leptin sensitivity. Metformin also reduces leptin-associated oxidative stress, smooth muscle cell proliferation, and matrix metalloproteinase-2 expression.
Beyond insulin resistance and cardiovascular disease, hyperleptinemia in T2DM patients is associated with other metabolic disorders and complications. Studies have reported a correlation between high leptin levels and the incidence, severity, and poor clinical outcomes of both ischemic and hemorrhagic strokes, possibly due to leptin’s influence on stroke risk through vascular inflammation and hemodynamic changes.
Recent studies suggest that leptin may also be implicated in cognitive function and neurological disorders such as Alzheimer’s disease (AD). A large cohort study in community-dwelling elderly individuals found that higher serum leptin levels were associated with a significantly reduced risk of cognitive decline compared to those with lower leptin levels. This relationship remained significant even after adjusting for body mass index (BMI), body fat percentage, and potential medical comorbidities, indicating that leptin may have a beneficial effect on cognitive function independent of metabolic factors. Leptin resistance, commonly observed in obese and elderly populations, likely due to decreased transport across the blood-brain barrier or downregulation of leptin signaling, may impair leptin’s neuroprotective and cognitive regulatory functions. This association between leptin resistance and cognitive decline is particularly pronounced in T2DM and obese patients.
Research shows that serum leptin levels in AD patients are significantly lower than in healthy individuals, independent of BMI. Low leptin levels may increase the susceptibility of AD patients to neuronal apoptosis, thereby worsening disease progression. Furthermore, a longitudinal study suggests that weight loss often precedes the onset of mild to moderate dementia, indicating that early weight reduction may relate to metabolic abnormalities rather than being a direct consequence of AD. Leptin’s anti-apoptotic properties and its role in modulating Aβ load suggest a protective effect in the pathogenesis of AD.
In foundational studies with mice and rats, leptin’s role in enhancing memory and learning has been further validated. Leptin significantly promotes synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), both of which are critical for spatial memory tasks. Additionally, direct administration of leptin into the dentate gyrus of the hippocampus enhances LTP and spatial memory in rats, while leptin injection into the CA1 region improves spatial memory and learning in mice. These findings support leptin’s positive role in maintaining cognitive function.
Scientists have identified potential mechanisms by which leptin might affect neuronal plasticity. Studies indicate that leptin enhances NMDA receptor activity, essential for memory formation and learning. Leptin may increase receptor function by promoting rapid NMDA receptor trafficking to the cell membrane, a mechanism similar to insulin’s effect on neurons. Additionally, leptin exhibits anti-apoptotic effects under stress, inhibiting neuronal apoptosis induced by oxidative stress or excitotoxicity. Leptin’s anti-apoptotic role in the hippocampus may involve enhancing mitochondrial anti-apoptotic functions, preventing early neuronal death and thereby preserving network stability and synaptic plasticity. Leptin also reduces brain Aβ levels by modulating apolipoprotein E (ApoE)-mediated Aβ uptake. In experimental models, leptin decreases Aβ load in the rat brain by up to 50\%, suggesting a protective role in the pathogenesis of neurodegenerative diseases like Alzheimer’s.
Recent research confirms leptin’s impact on cognitive function via the AMPK signaling pathway. Under severe dietary restriction, leptin mitigates the adverse effects on cognition, suggesting that the AMPK pathway may be a key regulatory mechanism in leptin’s influence on cognition. The AMPK pathway also modulates energy balance, aiding in neuronal function preservation under energy scarcity to prevent cognitive decline. Additionally, studies have found that female rats with higher systemic estrogen levels show increased sensitivity to leptin’s anorexigenic effects in the hypothalamus. This finding suggests that estrogen may enhance leptin signaling, impacting cognitive processes. The synergistic mechanism of estrogen and leptin may involve hippocampal synaptic plasticity modulation, thereby facilitating learning and memory.