Abstract
Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body’s metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a–f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the ‘longest form,’ and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.
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Introduction
Inactive leptin protein has 167 amino acids, but mature and functional leptin has 146 amino acids (Funcke et al. 2014). Hypothalamic neuropeptide Y and leptin hormone are essential for the energy homeostasis in the body (Kalra 2007). Congenital leptin deficiency is a rare cause of severe early-onset obesity (Frank et al. 2013; Wabitsch et al. 2015; Wasim and Fakhar 2015). In 1994, LEP gene was firstly discovered in mice (Zhang et al. 1994, Friedman 2010); the gene is also known as Ob gene owing to its relevance to obesity. It is located on chromosome 7, and its cytogenetic location is Chr:7q31.3 (Isse et al. 1995). Functions of LEP are the development of brain and modulation of carbohydrate metabolism in the body (Pasco et al. 2001). Leptin binds and activates leptin receptors which are encoded by a specific gene known as LEPR that is located on chromosome 1 having cytogenetic location at Chr:1p31. Leptin receptors have six isoforms (LEPR a–f), and all the isoforms are encoded by LEPR (Lee et al. 1996, Saeed et al. 2014b). These receptors belong to glycoprotein 130 (gp130) family of cytokines, and hence, any mutation in the LEP and LEPR has a major influence on metabolism, which can lead to obesity.
Obesity is a complex metabolic disorder (Khan et al. 2015; Locke et al. 2015; Leung et al. 2016; Xue and Ideraabdullah 2016), so heritability is not a fixed factor in the case of obesity. Environmental factors also influence individuals by observing their phenotype that can be explained by genotype. Prevalence data and mutations rate in LEP are reasonably high in Pakistani population, and it is reported that consanguineous marriages may have a role in obesity development (Saeed et al. 2014b). Two morbidly obese children of Pakistani origin were reported in 1997 to have mutations in the LEP (Montague et al. 1997). Similarly, two novel homozygous mutations in the LEPR were also reported in Pakistani subjects with obesity (Saeed et al. 2014b). Mutations in the LEP have been reported from different populations including that of Pakistani origin and are presented in Table 1.
Leptin is functional when it binds to its receptors. However, research indicates that binding of the leptin to its receptors can be inhibited by C-reactive protein (CRP), which is a serum leptin-interacting protein (SLIP). Different techniques have confirmed that human CRP in Ob/Ob mice has blocked the effects of leptin protein (Chen et al. 2006). Mutations are more common in the LEP as compared to its receptors gene, so leptin receptors are rare cause of severe early-onset obesity. However, recently, three novel mutations have been reported in the receptors gene in two unrelated affected girls with symptoms of severe obesity (Hannema et al. 2016). Recently, two homozygous mutations have been reported in LEPR from Pakistani population as well (Saeed et al. 2014b).
Function of LEP and LEPR
Leptin is an adipocyte-derived protein which was identified in 1994 in obese (ob/ob) mouse model. It is encoded by obese gene (Ob gene) another name for leptin gene and is responsible to regulate the balance between food intake and energy expenditure (Friedman 2010; Farr et al. 2014). Due to structural and functional similarities with pro-inflammatory cytokines such as interleukin 6 (IL-6), leptin is also termed a cytokine or adipocytokine/adipokine (Ahima et al. 2006). In obese humans, leptin deficiency/dysfunction is due to mutations in the LEP which is a rare genetic disorder and can be treated with exogenous administration of leptin (Gibson et al. 2004). It has been reported that twelve Pakistani, five Turkish, one Austrian, two Egyptian obese subjects as leptin deficient because of mutations in the LEP (Paz-Filho et al. 2010). Leptin is also increased in the serum of male obese asthmatic compared to non-obese asthmatic patients, which indicates that high leptin level is the key link between obesity and asthma (Shore 2010). Furthermore, leptin deficiency/resistance might cause inflammation, insulin resistance, liver steatosis, and adverse phenotype of lung complications like asthma associated with obesity (Mansuy-Aubert et al. 2013, Khan and Awan 2016).
Leptin deficiency/dysfunction may affect metabolism of the body, which is mainly due to the mutations in the LEP and LEPR (Farooqi 2005; Bluher and Mantzoros 2009). Leptin receptors have role in feeding regulation, and in the obesity development, these receptors are mainly found in the hypothalamus region of the brain (Cottrell and Mercer 2012). Such receptors also present in different tissues, but the longest receptor, LEPR-b, is located in the hypothalamus (Ronti et al. 2006; Saeed et al. 2014a).
Mutations in LEP and LEPR
Different mutations have been reported in the LEP (Table 1), one of such mutations is the guanine deletion (∆133G) in this gene. It was the first evidence for the congenitally leptin deficient subjects showing LEP that is responsible for the energy regulation (Montague et al. 1997). Leptin deficient (∆133G) child was treated with leptin replacement therapy (LRT) for 4 years with beneficial effects on fat mass, hyperinsulinemia, and hyperlipidemia (Gibson et al. 2004). To date, eleven mutations have been reported in LEP, which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X, c.104_106delTCA, c.135del3bp, c.398delG c.481_482delCT, and c.163C>T, and the prevalence of some of these mutations is presented in Table 1 (Funcke et al. 2014; Mazen et al. 2014).
On the other hand, mutations in the LEPR also lead to obesity as a family was reported with a mutation in the LEPR (Farooqi et al. 2007). Recently, two novel homozygous mutations have been reported in LEPR from Pakistani population, one is the splice site mutation and second is nonsense mutation in the exons 15 and 10, respectively (Saeed et al. 2014b). One more novel LEPR mutation (p.P316T) has been reported in two Egyptian cousins in the exon 6 of LEPR. Till now, just nine families have been reported with LEPR mutations (Mazen et al. 2011). Individuals with LEPR deficiency have the same phenotype as the leptin deficient subjects. Both LEPR and LEP deficient individuals exhibited rapid weight gain in the first few months of life, with severe hyperphagia and the endocrine abnormalities (Dubern and Clement 2012). Most recently, three novel mutations have been reported in the LEPR in two unrelated affected obese girls when latest genetic analysis techniques like whole-exome sequencing and targeted sequencing have been used for the mutational analysis in receptors gene (Hannema et al. 2016). As both LEP and LEPR have a role in energy expenditure, mutations in both affect body’s metabolism, leading to weight gain and severe obesity. Eleven reported pathogenic mutations in the LEP are shown in Table 1.
Benefit of Leptin Replacement Therapy (LRT)
Leptin deficiency might have negative energy balance in the individuals that may produce different conditions like lipoatrophy and anorexia nervosa. LRT is available for congenital leptin deficient subjects and highly useful for many of the conditions such as anorexia nervosa and for the obese individuals as well (Bluher and Mantzoros 2009). LRT is available for different conditions like hyperphagia and morbid, early-onset, or severe obesity. In some studies, children have shown positive response for LRT and with loss of their body weight up to 18 kg, so this therapy is beneficial for the leptin deficient subjects by preventing weight gain and morbid obesity (Farooqi 2005, Bluher and Mantzoros 2009). Leptin deficiency can be reversed by LRT (Farooqi et al. 2002), as it is reported that three obese individuals have been treated with LRT; treatment starts with specific range of doses of recombinant leptin at 0.01–0.04 mg/kg at regular basis, and their Body Mass Index (BMI) dropped down after 18 months of treatment. Reduction in BMI was due to loss of fat owing to this therapy (Licinio et al. 2004). Moreover, four Turkish patients have been reported who show significant positive effects by LRT (Paz-Filho et al. 2011).
Conclusion
Mutations have been reported in the LEP and LEPR. Different pathways have also been reported that affect the bioactivity of LEP and its receptors. Sequencing of the LEP is useful for the detection of any change in the DNA sequence, and other techniques like ELISA or LC–MS can detect the levels of circulating leptin in the blood. Until now, eleven pathogenic mutations have been reported in LEP, and most of the individuals were of Pakistani origin. Leptin is activated by its binding with specific receptors; however, mutations have been reported in the LEPR as well that cause severe obesity. Mutations have been identified in both the LEP and LEPR, but in both the cases, leptin therapy has positive impact on the patients. LRT prevents weight gain and severe obesity. This brief overview of leptin and its receptors provides a summary of information that eleven mutations have been reported in the LEP, and some mutations have been reported in LEPR, and also these mutations play a significant role in the body’s metabolism and mainly cause obesity. Hence, leptin and leptin receptors are suitable targets to tackle obesity in some patients where there are genetic defects to improve their lives.
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Wasim, M., Awan, F.R., Najam, S.S. et al. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity. Biochem Genet 54, 565–572 (2016). https://doi.org/10.1007/s10528-016-9751-z
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DOI: https://doi.org/10.1007/s10528-016-9751-z