INTRODUCTION:

Looking lean has become a trend among the people of twenty first century, but unfortunately most of them end up to be obese due to various reasons. Obesity causes several health problems, either independently or associated with some other diseases. The prevalence of obesity in the developed countries has increased by several folds over the last decades. Thus it has become important to gain knowledge about those factors that could control obesity, out of which leptin is an important one. Leptin levels fall during the weight loss and increases the activity of brain in areas related to emotional, cognitive and sensory control of food intake [1]. This hormone is derived from the adipocytes and the realization that the adipose tissue is not only a storage depot but also an important endocrine gland, has flashed the interest in the “lipostatic theory” [2]. Leptin signals the nutritional status from the periphery to the area of brain involved in the homeostasis of energy balance [3]. This review presents a better understanding of leptin’s role in obesity.

Leptin:

Leptin, a 167- amino acid protein which is produced by the leptin gene (LEP) [4], plays an important role in maintaining the body weight [5]. The word leptin is derived from the Greek word “leptos” which means “thin”. Leptin is a 16- KDa non- glycosylated protein product of ob gene [6]. In 1994, leptin was identified as the gene defect which is responsible for the obesity syndrome [7].

Leptin is mainly synthesized by the adipocytes [8] and initially it was thought that the main function of it was to signal the brain to inhibit the intake of food and decrease weight [9, 10]. The circulating leptin levels is directly proportional to the adipose tissue mass [11]. This hormone activates the hypothalamic centers which regulates the energy intake and expenditure[12]. Direct injection of leptin into the hypothalamus, would inhibit food intake and profoundly decrease weight and fat in animals lacking leptin [9, 13, 14].

Leptin plays a negative role in the feedback regulation in maintaining the body weight [15]. Recent researches states that the secretion of leptin is pulsatile in nature [16] and it follows the circadian rhythm. the highest levels of leptin secretions is observed during the nights [16,17]. Serum leptin levels are higher in women when compared to men [18, 19]. Two explanations are proposed for this sexual dimorphism. One, women have higher ratio of subcutaneous omental fat mass [20]. Two, the reproductive hormone status may account for the same [21]. Low levels of leptin would induce over feeding and would suppress the energy expenditure and vice versa for high levels of leptin [22]. Thus the major role of leptin is not “satiety signal” to prevent obesity in times of excess energy, but as a “starvation signaln to maintain adequate fat stores at times of energy deficit [23].

Defects in the leptin production cause severe obesity. The production of leptin is higher in cutaneous than in viscera [24-27]. Leptin also plays a major role in several other parts of the body like reproductive organs, mammary glands, immune system, gut, kidney and the lung[3].Recent studies has also spotted the rule of leptin in placenta [28].leptin circulates in the plasma is free form or in bound form. It binds with the leptin binding protein (LBP).

Leptin receptors:

Leptin interacts with six types of isoforms, one of which is ob Rb, the so called long form. All these are encoded by a single gene, LEPR (Leptin receptor) [29]. The only isoform that can signal intracellular membrane is the ob-Rb form. This form is present in hypothalamic nucleus[30]. The leptin receptor (ob-R) was first isolated from mouse choroid plexus by expression cloning [31]. The leptin receptor is a single membrane protein with structural similarity to the class I cytokine receptor family [32, 33] and these receptors binds Leptin with nanomolar affinity [31].

The hypothalamic arcuate nucleus acts as the major leptin signaling and resistance [34-36]. The arcuate nucleus , has within it two classes of neurons: one class reduces the food intake and other stimulates feeding behavior [37, 38]. Lack of Ob Rb is responsible for the obesity in db/db mice[39].

Leptin- mechanism of action:

Isoproterenol (40) and β₃ – adrenergic receptor reduces leptin mRNA and the circulating levels (41). Glucocorticoids increases leptin production in Vitro (42, 43). Leptin crosses the blood brain Barrier and reaches hypothalamus. Increased leptin would result in the negative energy balance (energy expenditure > food intake) and vice versa for the decreased leptin level [44]. Leptin secreted by adipocytes generally enters the brain at the choroid plexus. Once the leptin has bound to the OB-RB receptor, it activates the transcription factor stat 3 in the hypothalamus [45]. Extensive connections exist between the hypothalamus and other areas of brain. Leptin acts by activating specific centers and causes decrease in food in take, increase in energy expenditure and fat metabolism, influence Glucose metabolism and alters the Neuroendocrine function [46].

Obesity:

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems[47, 48]. People are considered obese when their body mass index (BMI), a measurement obtained by dividing a person's weight in kilograms by the square of the person's height in metres , exceeds 30 kg/m² [49]. It is defined by body mass index (BMI) and further evaluated in terms of fat distribution via the waist–hip ratio and total cardiovascular risk factors [50].BMI is closely related to both percentage body fat and total body fat [51]. Obesity occurs as a result of imbalance between the food intake and energy expenditure. This leads to the accumulation of fat in adipose tissue, liver, muscle, pancreatic islets and other organs. [52]. Obesity tend to increase the risk of diabetes, coronary heart disease, fatty liver, gall stones, sleep apnea, arthritis and cancer thees reducing the life spam of an individual [53]. Obesity also causes polycystic ovary syndrome in women [54].

Factors influencing obesity:

Body weight is influenced by interaction between genetic, environmental and psychosocial factors [55] some of them are,

· Genetics

· Environmental factors

· Energy expenditure

· Energy intake

· Culture

· Fetal nutrition

Leptin in obesity:

Initially leptin was considered to act as a signal indicating the abundant fat stores to the hypothalamus thus limiting the energy intake and increasing the energy expenditure. But the primary role of leptin is to get adapted to the negative energy balance. A drop in circulating leptin level increases hunger. Leptin directly regulates the adipose tissue mechanism by inhibiting lipogenesis and stimulating lipolysis [56].

Circulating leptin concentration elevates in obese individual and falls down after the weight loss. Deficiency of this hormone leads to obesity. An evidence for this was brought out in the year 1997, when two children, who were the cousins of the Pakistan origin, were homozygous for a frame shift mutation in ob gene, which resulted in the undetectable circulating leptin and severe obesity [57]. Administration of recombinant human leptin for 24 weeks induces significant, but variable degrees of weight loss [58]. Glucocorticoids interfere with leptin’s interaction with its receptors and produce leptin resistance [59-62].

In the lack of adipocyte hormone leptin, ob/ob mice develop severe obesity as a result of increased food intake and suppressed energy expenditure [63]. The ob/ob mouse failed to produce humoral factors which inhibits food intake, whereas db/db mouse produce this factor and thus does not respond to it [64]. Administration of leptin to obese human subjects brought about only small changes in body weight. Therefore testing of leptin receptor function would help to understand the pathogenesis of obesity [65].

During weight gain:

Increased food intake and decrease energy expenditure

Fig. 2: Role of leptin in obesity

Treatment:

It has been proved that treatment with leptin reduces weight in mammalian species, including the vat, the dog and the monkey.[66]recent reports project that daily subcutaneous administration of leptin over 9 month to a leptin deficient patient, would decrease body weight by 14.7Kg and also improves the metabolic profile [67]. Direct administration of leptin into cerebrospinal fluid is very effective but the drug must be delivered safely [68].Gene therapy also may provide an efficient alternate in delivering leptin. Adeno virus and Adeno- associated virus vectors exerts potent weight reducing effects in rodents [69, 70]. Thus leptin finds its way as anti-obesity drug in the clinical trials.

CONCLUSION:

Obesity is posing a major and serious health problem in societies of developing and developed countries. Leptin acts as a vital tool in fighting against obesity. Leptin signaling plays a predominant role by acting on the accurate nucleus to control satiety and thus the body weight. Hence it prevents many diseases such as hypertension, diabetes mellitus much before their occurrence.

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Received on 26.09.2014 Modified on 20.10.2014

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