Trajectory of leptin and leptin receptor in vertebrates: Structure, function and their regulation

Highlights

• Discovery and structural biochemistry of leptin and leptin receptor in vertebrates.

• Tissue distribution of leptin and its receptor across vertebrates.

• Role of leptin in control of feeding, metabolism, immunity and reproduction.

• Regulation of leptin system in fishes, herptiles, birds and mammals.

Abstract

The present review provides a comparative insight into structure, function and control of leptin system in fishes, herptiles, birds and mammals. In general, leptin acts as an anorexigenic hormone since its administration results in decrease of food intake in vertebrates. Nonetheless, functional paradox arises in fishes from contradictory observations on level of leptin during fasting and re-feeding. In addition, leptin is shown to modulate metabolic functions in fishes, reptiles, birds and mammals. Leptin also regulates reproductive and immune functions though more studies are warranted in non-mammalian vertebrates. The expression of leptin and its receptor is influenced by numerous factors including sex steroids, stress and stress-induced catecholamines and glucocorticoids though their effect in non-mammalian vertebrates is hard to be generalized due to limited studies.

Introduction

Leptin, one of the key hormones of appetite regulation, was discovered as a result of spontaneous mutation in autosomal obese (Ob) gene that led to enormous weight gain concomitant with hyperphagia in mice (Ingalls et al., 1950). These phenotypes were similar to another strain of mice that had been designated as diabetic (Db/Db) (Hummel et al., 1966). A set of parabiosis experiments between Ob/Ob and Db/Db mice revealed that Db/Db mouse overtly produced satiety factor but was unable to respond to this factor probably due to non-functional receptor. On the other hand, Ob/Ob mouse was unable to produce but able to respond to the satiety factor. It was thereby suggested that Ob encodes for the satiety factor while Db codes for its receptor (Coleman and Hummel, 1969; Coleman, 1973). The Ob gene was cloned employing physical and genetic mapping techniques (Zhang et al., 1994) and shown to translate a protein named leptin (Lep) (Halaas et al., 1995). The receptor for leptin (LEPR) was first identified in the choroid plexus of mouse by expression cloning technique (Tartaglia et al., 1995) and interestingly, Lepr gene was found to be Db gene (Chen et al., 1996; Lee et al., 1996). Among non-mammalian vertebrates, prior to the cloning, existence of leptin was demonstrated immunocytochemically in various tissues of fishes (Johnson et al., 2000), amphibians (Buono and Putti, 2004) and reptiles (Niewiarowski et al., 2000; Muruzábal et al., 2002). The leptin ortholog was first discovered in pufferfish Takifugu rubripes (Kurokawa et al., 2005) and thereafter, in a number of teleosts (Denver et al., 2011). The reason for delayed discovery has been attributed to poor conservation of its primary sequence. As far as discovery of lepr in non-mammalian vertebrates is concerned, it was first cloned in chicken (Horev et al., 2000; Ohkubo et al., 2000) much prior to cloning of avian lep gene (Friedman-Einat et al., 2014; Huang et al., 2014; Prokop et al., 2014). The reasons that made cloning of avian lep difficult were poor sequence conservation (≤ 30%), exceptionally high (upto 80%) guanine-cytosine percentage (Friedman-Einat and Seroussi, 2019), absence of chromosomal fragment where leptin gene is localized (Pitel et al., 2010) and undetectable plasma leptin (Yosefi et al., 2010).

The physiological role of leptin and regulation of leptin system have been well explored in mammals and reviewed from time to time (Fried et al., 2000; Ramsay and Richards, 2004; Wrann and Rosen, 2012; Park and Ahima, 2015; Aragonés et al., 2016; Procaccini et al., 2017; Münzberg and Heymsfield, 2019). Apart from canonical role in feeding, leptin is reported to affect several physiological functions, importantly, reproduction, puberty, immunity and metabolism (Park and Ahima, 2015; Procaccini et al., 2017; Münzberg and Heymsfield, 2019). Further, various factors such as sex steroids, corticosteroids, prolactin, cytokines, nutrients, beverages and stress have been unearthed in regulation of leptin and leptin receptor (Fried et al., 2000; Ramsay and Richards, 2004; Wrann and Rosen, 2012; Aragonés et al., 2016). However, structural, functional and regulatory aspects of leptin and its receptor in non-mammalian vertebrates are relatively less studied (Deck et al., 2017; Londraville et al., 2017). To better comprehend the comparative physiology of leptin in vertebrates, a comprehensive picture of different aspects of leptin physiology and its regulation from fishes to mammals have been discussed in this review article.