1. Introduction

It is over 50 years since Hervey performed ground-breaking parabiosis experiments which suggested that a circulatory factor regulates food intake and body weight ^[1]. This factor has since been identified as the 16 kDa ob gene product, leptin, which is derived from the Greek word leptos, meaning thin ^[2]. The major site for the production of leptin is white adipose tissue, although leptin is also made in various other peripheral tissues, including skeletal muscle, placenta and mammary epithelium. The circulating plasma levels of leptin directly correlate to overall body fat content ^[3]. Although leptin is predominantly produced by peripheral tissues, it readily gains entry to the brain via a saturable transport process at the blood–brain barrier or via the cerebrospinal fluid ^[4]. Within the CNS, specific hypothalamic nuclei such as the arcuate nucleus and ventromedial hypothalamus are key targets for leptin. After a meal, circulating leptin levels increase, leading to a rise in the CNS levels of leptin which in turn signals a feeling of fullness. In contrast, after periods of starvation or fasting, the circulating leptin levels fall, which acts as a stimulus for feeding ^[5].

Studies in this area have been aided by the availability of rodents with naturally occurring mutations in the leptin and lepR genes. Mutations in the ob gene have been shown to underlie early-onset obesity, hypothermia, and hyperphagia in mice. Thus, in ob/ob mice, there is a lack of leptin as a truncated leptin protein is generated that is unable to be secreted. In a different leptin-deficient mouse strain (ob^2J/ob^2J), a transposon is integrated into the ob gene, thereby preventing ob mRNA synthesis. Interestingly, ob gene mutations rarely occur in humans. However, cases of morbid obesity identified in families from Pakistan and Turkey have been linked to specific mutations in the ob gene. The low incidence of leptin-specific mutations in humans indicates that genetic abnormalities in the leptin system are not the principal route for the development of obesity in humans.

2. Leptin Receptors

2.1. Leptin Receptor Isoforms

Leptin produces its biological effects via activating the leptin receptor (LepR). Tartaglia and colleagues first isolated LepR from the choroid plexus, and six isoforms of the receptor have been identified (LepRa-f) ^[6]. The isoforms differ with respect to their C-terminal domain length, which in turn influences the signalling capacity of the different LepR isoforms. It is widely accepted that the long-form (LepRb) is the predominant signalling competent isoform due to the extended length of its C-terminal domain. Conversely, the short isoforms (LepRa,c,d,f) have shorter C-terminal domains and limited signalling capacity. LepRe is distinct as it lacks a transmembrane domain but it is thought to be a route for transporting leptin in the plasma, as it still retains leptin-binding capacity.

2.2. Leptin Receptor-Driven Signalling

LepRs are members of the class I cytokine receptor superfamily which signal via association with janus tyrosine kinases (JAKs) ^[7]. Leptin binding to its receptor promotes phosphorylation and subsequent activation of JAK2, leading to recruitment and stimulation of various downstream pathways including phosphoinositide 3-kinase (PI3K), ERK, and signal transducers and activators of transcription (STAT3). LepR signalling can be terminated via activation of SOCS1-3 (suppressor of cytokine signalling), which bind to phosphorylated JAK2, thereby limiting LepR-driven signalling ^[8]. In hippocampal neurons, activation of PI3K, ERK and STAT3 are implicated in LepR-driven regulation of synaptic function (Figure 1) ^[9].

Figure 1. Leptin receptor-driven signalling in neurons. The key signalling pathways activated following leptin binding to leptin receptors (LepRs) and subsequent activation of janus tyrosine kinase (JAK)2 are shown including signal transducers and activators of transcription (STAT3), Ras-Raf-MEK-MAPK and phosphoinositide 3-kinase (PI3K), which ultimately lead to gene transcriptional changes or altered ion channel function. LepR signalling is terminated following the production of suppressor of cytokine signalling (SOCS)3.

In rodents, LepR gene mutations result in leptin-insensitivity, which ultimately leads to development of early-onset obesity as well as several endocrine-related impairments ^[2]. In db/db mice, a truncated form of LepR is produced which is unable to signal via the conventional JAK-STAT signalling pathway. Conversely, in fa/fa rats, a single point mutation occurs that renders all the LepR isoforms signalling incompetent ^[2]. In a manner similar to the ob gene mutations, the incidence of human LepR gene mutations is also extremely low.

2.3. Leptin Receptor Expression in the CNS

In accordance with leptin’s pivotal role in controlling energy homeostasis, LepRs are highly expressed in specific regions of the hypothalamus that govern food intake and body weight, such as arcuate nucleus and ventromedial hypothalamus ^[10][11]. Additionally, high levels of LepR expression are observed in many other brain regions, including the hippocampus and cortex ^[12][13]. This pattern of LepR expression in the CNS suggests potential important roles for leptin in higher brain functions. Indeed, early studies involving leptin-deficient (ob/ob) mice demonstrated that absence of leptin resulted in neurodevelopmental abnormalities, with specific impairments detected in hippocampal and cortical brain regions ^[14]. These deficits were readily reversed by leptin replacement, suggesting a role for leptin in neuronal development. In support of this hypothesis, a surge in leptin is observed during the critical period of postnatal development ^[15]. Subsequent studies in this area have identified that this postnatal leptin surge plays a critical role in development of key hypothalamic synaptic connections involved in control of energy homeostasis ^[16]. However, increasing evidence indicates that the modulatory effects of leptin are not restricted to early postnatal stages of development, as leptin is reported to markedly influence the functioning of the hippocampus in adulthood and during ageing. Thus, in adult, tissue treatment with leptin has a major impact on the cellular processes underlying hippocampal learning and memory, which has led to the proposal that this hormone acts as a potential cognitive enhancer ^[17][18]. In support of this possibility, deficits in hippocampus-specific processes, such as spatial learning and memory, accompany insensitivity to leptin ^[19][20].

This entry is adapted from the peer-reviewed paper 10.3390/ph14010052