The Effects of Leptin Replacement on Neural Plasticity

Abstract

Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia’s encephalopathy

“…There is a reasonable body of scientific evidence suggesting that leptin has a beneficial effect on central nervous system function [11,12] and on some neurodegenerative disorders, like Alzheimer's disease (AD) [13,14]. In addition to its well-known effects on the regulation of food intake and on energy expenditure in the hypothalamus [15], leptin can affect neurogenesis, synaptogenesis, neuronal excitability, axon growth and dendritic morphology and can have neuroprotective effects [12,[16][17][18][19][20][21]. Moreover, leptin regulates the synapse morphology of hippocampal neurons [22] and modulates the development of oligodendroglial cells [23], which may contribute to structural changes in gray matter.…”

“…In addition, leptin may help prevent neuronal death in neurodegenerative disorders [12]. For example, in transgenic mice models of AD, leptin replacement therapy (LRT) results in significant cognitive improvement [13] and reduces the brain amyloid-beta peptide load [14].…”

Brain nutrition-orthomolecular aspects

“…DHEA increases the expression of the glial cell-derived neurotrophic factor [GDNF] invigorating the dendritic arborisation and neurogenesis [93,94]. Leptin, an adipose-like adipokine, known by its several roles in food intake and energetic expenditure metabolism, can also regulate apoptosis, protect against oxidative damage and stimulate neuroplasticity, axon growth, synaptogenesis and proliferation of hippocampal and dendritic stem cells [95][96][97]. About other hormones, it's a major recognition the widerange role of the steroids hormones on the nervous system, which contains specific receptors from the most important peripheral organs like ovaries, testes and adrenal cortex [98].…”

Cord Leptin is Associated with Neuropsychomotor Development in Childhood

“…Apart from the hypothalamus, leptin and its receptors are widely expressed in brain regions of the central nervous system (such as the hippocampus, cerebral cortex, basal ganglia, brain stem, and cerebellum), regulating numerous functions, including cognition and memory processing . Cognitive performance is impaired in leptin‐deficiency models, whereas leptin replacement improves memory and learning in mice and, in some cases, has improved neurocognitive development in patients with congenital leptin deficiency . Leptin has been found to be a crucial regulator of central nervous system development in both rodents and humans .…”

“…performance is impaired in leptin-deficiency models, whereas leptin replacement improves memory and learning in mice and, in some cases, has improved neurocognitive development in patients with congenital leptin deficiency (6). Leptin has been found to be a crucial regulator of central nervous system development in both rodents and humans (7).…”