Leptin: role over central nervous system in epilepsy

The central nervous system (CNS), specifically the hypothalamus, acts as a sensor of storage and energy expenditure. Adipocytes, the most important functional unit of adipose tissue, secrete adipokines, such as leptin, that regulate energy balance [1]. Although the role of leptin at the hypothalamic level to regulate food intake and energy balance is well established, its participation on higher brain functions remains to be elucidated. For instance, there is evidence showing that leptin can act both as anticonvulsant and convulsant trigger [1].

Epilepsy is a chronic neurological disorder experienced by approximately fifty million people around the world. Its prevalence in the general population is 4–10 per 1000 people, while in low and middle-income countries is higher (7–14 per 1000 people) [2]. Whereas active epilepsy (defined as a history of more than one unprovoked seizure and either recent seizures in the previous 5 years or current use of antiepileptic medication), is 12.4 per 1000 people ranging from 5.1/1000 to 57/1000 [3–5]. The incidence of epilepsy range between 30 and 50 per 100,000. In 2012, 20.6 billion disability adjusted life years (DALYs) were due to epilepsy [2].

The objective of this article was to analyze the possible effects of leptin on the pathophysiology of epilepsy, comparing the findings of animal models, which demonstrated both convulsive and non-convulsive actions. To contextualize the review, we described the molecular characteristics of leptin, its various isoforms, the receptors in the central nervous system, the signaling pathway in nervous cells, the role and functions of leptin within the CNS affecting higher brain functions, and/or showed the specific actions related to the mechanism of epilepsy.

A review of literature was carried out. The following databases were consulted: Pubmed, Science Direct, Elsevier ResearchGate and Scielo. Eligibility criteria were: experimental studies, reviews and systematic review articles; that were selected if the publication date between January 1997 and January 2018; restricted to non-human studies and articles published in English, Spanish and Portuguese. Research was made through the Medical Subject Headings (MESH) terms: MeSH keywords in Pubmed: (((“Epilepsy”[Mesh]) AND “Leptin”[Mesh]) OR “Adipose Tissue”[Mesh]) OR “Hypothalamus”[Mesh]. The same search terms were adapted for Science Direct, Elsevier ResearchGate and Scielo electronic databases. The corresponding Health Sciences Descriptors in Spanish (DeCS) terms were also used. Exclusion criteria were studies outside the range of proposed dates and studies made in humans.

Two authors (LMM, AGN) independently evaluated the eligibility of all studies by checking the title and the abstract to determine whether they met all of the inclusion criteria. Disagreements were resolved by discussion or consultation with other authors (AVM). When they were ambiguous, the complete articles were analyzed to determine their pertinence. A total of 226,925 articles were identified through databases searching using the MESH an DECS terms (Fig. 1). Consecutively, the articles were selected based on title, abstract, and, in text information. Based on these criteria, a total of 65 articles were chosen.

As a meta-analysis was not performed due to the characteristics and heterogeneity of the articles, a narrative report was done extracting the most important information of each article.

Leptin, a 16-kDa protein encoded by the Ob gene, regulates body weight, reduces appetite, and controls food intake. Insulin, glucocorticoids, leptin and other hormones regulate expression of this protein. It appears that several metabolic actions are controlled through FOSL2, a key transcription factor that regulates leptin expression in the adipocyte [6–8].

There are six isoforms of the leptin receptor (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re and OB-Rf) that result from RNA alternative splicing. According to their domains, are classified in short, long and secreted [9]. Ob- Rb stands out as the only receptor type showing a full-length intracellular domain containing 304 residues, which gives it the ability to activate intracellular signaling cascades. Once leptin binds to Ob-Rb, it elicits the auto-phosphorylation of Janus kinase -2 (JAK- 2), a non-receptor tyrosine kinase that is associated with the Ob-Rb receptor. Thereafter, JAK- 2 phosphorylates tyrosine (Tyr) residues of the intracellular domain of Ob-Rb, and depending on the Tyr residue that is phosphorylated it can trigger different types of intracellular responses [1, 9] (Fig. 2).

In the case that Tyr 985 is phosphorylated, it will lead to the recruitment of Src homology 2 domain (SH2), triggering a signaling cascade mediated by extracellular signal-regulated kinase (ERK) [9]. The SH2-containing tyrosine-specific protein phosphatase (SPH2), and “SH2 domain-containing adaptor, the growth factor receptor-binding protein” (GRB2), enable ERKs phosphorylation [10]. Its activation has been related to energy homeostasis, as long as its blockage incurs in a disruption in the induction of sympathetic activation of BAT and a deregulation of its anorexic, and weight controlling actions [11].

On the other hand, if Tyr 1077 residue is phosphorylated, it leads to signal transducer and activator of transcription 5 (STAT -5) activation, whereas if Tyr 1138 residue is phosphorylated, it will lead to STAT 3 activation. STAT phosphorylation leads to the dimerization and its subsequent translocation to the nucleus, coordinating the transcription of genes involved in energy balance such as proopiomelanocortin (POMC) [1, 9]. POMC is a protein that can be cleaved to render the anorexigenic α-melanocyte stimulating hormone (α -MSH), which constitutes the major target of this pathway [9]. It is noteworthy to remark that STAT 3 also plays a significant role in controlling the transcription of genes that are implicated in leptin signaling, such as suppressor of cytokine signaling 3 (SOCS3), a key negative regulator of leptin effects, by inhibiting leptin- STAT3 signaling [12].

Activation of phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) by the Insulin Receptor Substrate complex, is also induced. PI3 K mediates the signaling of leptin in hypothalamic neurons, regulating neuro electrical effects on POMC neurons. This enzyme phosphorylates PIP2 (phosphatidylinositol-4,5-bisphosphate) and forms PIP3 (phosphatidylinositol-3,4,5-triphosphate), which links the activity of PI3 K with important downstream pathways, like Akt-FoxO1 and Akt-mTOR [9]. Interestingly, as demonstrated, leptin can inhibit different forms of epileptiform-like activity via PI3 K pathway [13].

The activity of Akt within the Akt- mammalian target of rapamycin1 (mTORC1) pathway allows the activation of mTORC1 mainly by various mechanisms that have been subject to extensive study. mTOR activation is related with leptin action in the hypothalamus [14]. Leptin increases hypothalamic mTOR activity, and this the serine-threonine kinase, through its downstream target Ribosomal protein S6 kinase beta (S6K1), phosphorylates α2-AMPK. In consequence the activity of leptin decreases food intake and body weight. Additionally, mTOR mediates the anorexigenic, sympathetic and cardiovascular effects of leptin [9].

As it was mentioned above, leptin plays key roles within the hypothalamus to control food intake and energy expenditure. However, there is also evidence suggesting that leptin could be involved in other neurological processes in extra-hypothalamic sites. Interestingly, within the hippocampus leptin was associated with both anticonvulsant and convulsant effects, and it was also shown to act as neurotrophic factor that promotes neurogenesis [7, 15–17].

Leptin has been strongly associated with the regulation of neuronal excitability in different regions of the CNS [18, 19]. It modulates cell excitation by activating large conductance Ca⁺-activated potassium channels (BK channels) within the hippocampus and by stimulating ATP-sensitive potassium channels (KATP channels) during its regulatory metabolic functions within the hypothalamus and insulin-secreting cells [20–22]. The latter, highlights the anorexigenic leptin functions that are well described in the literature. However, mounting evidence also suggest other central actions of leptin in multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, that remain to be better understood [23–25].

There is evidence showing association between leptin and high brain functions, such as cognition and memory; for example, higher leptin levels are associated with a lower risk of incident dementia and Alzheimer’s disease (AD) [26]; leptin improves memory and serves as disease modifying therapeutic in transgenic mouse models of AD [27]; leptin receptor-deficient rodents have impairments in spatial memory and alterations in LTP and LTD in hippocampal CA1 neurons[28]; physiological increases in leptin levels facilitate the CaMK II activity in the hippocampus, which induces LTP, contributing to memory and learning[29]; and leptin facilitate spatial learning and hippocampal LTP in mice [30]. In vivo studies in rodents reported that leptin can increase the proportion of dendrites enabling morphological changes that can promote the formation of new synaptic connections within the hippocampus [17, 31]. The latter suggested that leptin may have an important therapeutic role in neurodegenerative diseases such as epilepsy. In fact, it has been established that the effects of leptin-based therapeutic strategies are potentially useful for patients with diverse diseases, besides congenital metabolic leptin deficiency disorders, such as mood disorders, Alzheimer’s disease and autism [30, 32–34].

Interestingly, some studies have explored the role of astrocytes in the activity of leptin on the CNS. These glial cells express various Ob-R subtypes. When some of them are overexpressed, changes have been demonstrated in leptin permeability through an in vitro blood brain barrier system, suggesting that astrocytes might be involved in the entrance of leptin into the CNS [35]. In mice, with specific mutations that inhibit expression of Ob-R in astrocytes (ALKO Mice-astrocyte specific leptin receptor knockout mice) studies have shown that astrocytes can intervene significantly in neuronal leptin-induced signaling [36].

Jayaram et al. [37] found that leptin may have glioprotective effects in a mouse model of seizures induced by pilocarpine administration. This model found that ALKO mice had a lower survival rate and that administration of leptin, under gliotoxicity when exposed to high levels of glutamate, exerted a protective effect on astrocytes [37]. These results suggest that leptin can have a protective role against excitotoxicity when presented during epilepsy.

At this point, it is important to note that the peripheral effects of leptin may have relevant implications on susceptibility to epilepsy. The dysfunction of the adipose tissue and the hormones that it produces, such as leptin, supposes a susceptibility to neurodegenerative diseases associated with obesity and metabolic disorders, since the neuroprotective effects that have been evidenced in the actions of leptin could be influenced by the resistance to leptin that is characteristic of disorders such as obesity, decreasing it’s neuroprotective effect and contributing to the pathogenesis of different neurodegenerative diseases, such as AD [38, 39]. In addition, obesity causes metabolic changes that alter the expression of leptin receptors in astrocytes, generating underlying alterations in the functions of glial cells that would have serious implications for leptin homeostasis as previously mentioned [36, 40]. In fact, models with adult-onset obesity mice have shown that obesity induces an increase in ObR levels in astrocytes and ObRb mRNA in the cerebral microvasculature [41], and that astrocytes play regulatory roles on the dynamics of leptin in the hypothalamus, since its inhibition improves the signaling and uptake of leptin by neurons [42]. Finally, it should be noted that obesity implies the occurrence of a sufficiently important level of peripheral inflammation, which could be mediated by the action of leptin and could contribute significantly to the development of neuroinflammation and oxidative stress in the central nervous system, increasing the susceptibility to the occurrence of neurodegenerative diseases, such as epilepsy [39, 43, 44].

It would be interesting to determine the possible effects that antiepileptic drugs (AEDs) have on the role of leptin on CNS. Weight gain is associated with changes in secretion and behavior of leptin and it is a major side effect of these drugs. It is relevant to assess whether the actions on neuronal excitability of this hormone, both positive and negative, could be involved in the evolution of epilepsy before consumption of AEDs [45–48].

In recent decades, the relationship between the effect of leptin on the CNS and epilepsy has been recognized as a new and viable association that could lead to future effective alternatives to treat this disorder. Experimental animal studies conducted around this association have generated results that begin to unravel the potential therapeutic effects of leptin on metabolic and neurodegenerative diseases [1, 18, 19].