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Online First                                                                                                                      Indian J Pharm Drug Studies | 1  

Review Article 

Decoding Leptin: Unraveling the Role of Leptin Signaling in the Battle against 

Obesity 

Soumyadip Singha1, Soumyadip Nayak2, Rahul Bishayee2, Pritam Sarkar3, Priyanka Ghosh3, Udita 

Dutta4, Poulomi Mishra5 

From, 1Lecturer, Pandaveswar School of Pharmacy, Pandaveswar, West Bengal, India, 2PG Student, Department of Pharmacology, 

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India, 3UG Student, Department of  

Pharmacy, School of pharmacy, Seacom Skills University, Bolpur, West Bengal, India, 4UG Student, Department of  Pharmacy, 

Eminent College of Pharmaceutical Technology, Moshpukur, Barbaria, Paschim Khilkapur, Barasat, Jagannathpur, West Bengal, 

India. 5Assistant Professor, Pandaveswar School of Pharmacy, Pandaveswar, West Bengal, India 

ABSTRACT 

Obesity represents a major global health crisis, linked to a spectrum of metabolic disorders, including diabetes, cardiovascular 

diseases, and hypertension. Leptin, a hormone predominantly produced by adipose tissue, plays a critical role in regulating energy 

balance, appetite, and metabolism. Historically, leptin was believed to be a cornerstone in the management of obesity due to its ability 

to suppress appetite. However, the effectiveness of leptin therapy has been limited by the phenomenon of leptin resistance in obese 

individuals. This review, titled "Decoding Leptin: Unraveling the Role of Leptin Signaling in the Battle Against Obesity," aims to 

delve into the molecular intricacies of leptin signaling pathways and their implications in obesity management. We explore the 

mechanisms underlying leptin resistance, the impact of leptin on neuroendocrine pathways, and the potential for resetting leptin 

sensitivity as a therapeutic strategy. Additionally, we discuss recent advances in therapeutic approaches aiming to enhance leptin 

sensitivity or mimic its effects, including novel pharmacological agents and lifestyle modifications that influence leptin signaling. By 

providing a comprehensive overview of current research and emerging therapies, this review seeks to illuminate the path forward in 

leveraging leptin signaling for more effective obesity interventions. 

Key words: Leptin Resistance, Obesity Management, Therapeutic Strategies, Neuroendocrine Regulation 

besity can be defined as a condition which can be 

characterized by excessive accumulation of body fat 

which has the capability to show negative impact of 

health, in general a person could be said that he or she is 

suffering from obesity by checking the BMI over 30 kg/m3[1]. 

There are Certain East Asian Countries they apply lower value 

for defining the obese condition. Obesity can be linked with 

various other health risk factors, such as cardiovascular 

diseases, Type II Diabetes, Obstructive sleep apnea, certain 

cancers, osteoarthritis, obesity can also be influenced by a 

reciprocal relationship by depression.  

Obese condition for children ranging between the age of 5-

19, can be defined with the BMI with two standard deviations 

above the median their age group [2], and for the age group 

below the age of 5, the obese condition is considered to be the 

three-standard deviation above the median. The assessment of 

fat distribution and cardiovascular risk factorcould be done by 

subdividing BMI by the CDC [3]. When it comes to the 

etiological factors of obesity, excessive calorie intake and  

Access this article online 

 

Received –  24th May 2024 

Initial Review –  30th September 2024 

Accepted – 28th October 2024 

Quick Response Code 

leading a sedentary life plays major role, while the genetics 

also have some role when it comes to obesity with certain 

genes showing influence towards susceptibility to obesity 

[6][9]. In addition, there are certain drug metabolism system 

which also contributes to the condition of obesity, particularly 

fat-soluble drugs, like anti-tuberculosis medications [10]. The 

increase risk of obesity is also accompanied with the treatment 

for certain physical and mental illness like psychiatric disorder 

[11]. Finally, the contribution of the hormone leptins plays the 

vital role in obesity. Leptin is a hormone with helps in 

regulating the intake of food and energy usage. Obsess 

condition may occur when the hormone leptin have lost its 

ability to signal the brain about proper functioning of food 

intake and usage of energy.  

Leptin and its Receptors: Leptin is a neurohormone that acts 

in the hypothalamus to regulate energy balance and food 

intake [12]. Recessive mutations in the leptin (obese, ob) or its 

receptor ObR gene result in profound obesity and type II 

diabetes mellitus. Further studies demonstrated that in  

__________________________________________________ 

Correspondence to: Poulomi Mishra. Pandaveswar School of 

Pharmacy, Pandaveswar, West Bengal, India. 

Email: mishrapoulomibeliatore@gmail.com 

O 

mailto:mishrapoulomibeliatore@gmail.com


Singha et al.                                                                                     Leptin: Its Crucial Role in the Fight Against Obesity 

Online First                                                                                                                      Indian J Pharm Drug Studies | 2  

addition to its role as a neurohormone, leptin can modulate 

immune response, fertility, and hematopoiesis, acting as a 

mitogen, metabolic regulator, or pro angiogenic factor [13]. 

The central regulation of food intake and energy expenditure 

is mediated through the binding of leptin to its receptor ObR, 

a type 1 cytokine receptor. Several isoforms of ObR have been 

described as a result of alternative mRNA splicing leading to 

several short isoforms (ObRa, ObRc, ObRd, and ObRf), one 

long isoform ObRb with a long cytosolic C-terminus tail and 

one soluble isoform Obre [14].  

Hence, ObR isoforms differ in the length of their 

Intracellular region but share identical extracellular domains. 

While short isoforms are ubiquitously expressed, ObRb 

expression is more restricted with high levels in hypothalamic 

nuclei such as the arcuate nucleus (ARC). The hypothalamic 

ARC has an important role in the development of leptin 

resistance. Accordingly, exposure of rodents to a high-fat diet 

rapidly decreases the phosphorylation of STAT3 in the ARC or 

the ventral tegmental area (VTA), while leptin-sensitivity is 

simultaneously maintained in some other hypothalamic nuclei. 

While the biological function of the short isoforms is still 

elusive, it is well established that Obftb is the main isoform 

responsible for the effect of leptin on body weight control. The 

weight lowering properties of leptin via ObRh has been 

suggested to be centrally mediated.  

Once activated after leptin binding, ObRh is able to trigger 

various signal transduction pathways. Activation of the Janus 

tyrosine kinase 2 (JAK2)/signal transducer and activator of 

transcription 3 (STAT3) pathway leads to an increase of 

anorexigenic signals and a decrease of orexigenic signals [15]. 

Leptin is also able to activate the insulin receptor substrate 

(IRS)/phosphatidylinositide 3-kinase (PI3K) pathway, 

essential for the regulation of glucose homeostasis [16]. 

Moreover, leptin inhibits the energy 10 sensor adenosine 

monophosphate activated protein kinase (AMPK) in the brain, 

to decrease eating. The activation of extracellular signal 

regulated kinase (ERK) is another pathway mediating the 

anorectic action of leptin in the hypothalamus. 

Leptin Expression In Obesity: Early onset obesities has the 

capability to form rare genetic mutations which can hamper 

leptin signaling which might lead to congenital leptin 

deficiency or leptin resistance. Hyperleptinemia and resistance 

to reducing body mass is the general characteristics of leptin 

resistance [5][6][17][18]. A person is leptin resistant, can only 

be said with the presence of leptin in plasma at higher amount, 

high amount of leptin in blood plasma certainly corelates with 

body fat percentage. Several weight loss studies have revealed 

that the level of leptin can decrease initially and then gradually 

rise with continued weight loss.  

Matheny et al.’s research put light on leptin resistance can 

be induced in the arcuate nucleus (ARC) and ventral 

tegmental are (VTA) of the brain with high fat diets, while 

when it comes to medial basal hypothalamic region it retains 

sensitivity [20][21]. The critical role of ARC in leptin can be 

indicated by targeting downregulation of leptin receptor 

expression in the ARC promoting diet-induced obesity. 

Activation of SOCS3 and STAT3 resistance to leptin in neuron 

such as pro-opiomelanocortin (POMC) and AgRP in rodents 

with high-fat content diet.  

While AgRP neurons shows increased sensitivity towards 

leptin when the rodents are shifted to low-fat content diet. 

Polymorphism in the crystalline structure of the leptin (ob) 

and leptin receptor (LEP-R) genes which has the capability to 

disrupt leptin functions resulting in obesity [22][23][24]. The 

polymorphism of LEP-2548 G/A are widely studied in 

humans for understanding obesity. A protein quantitative trait 

locus (pQTL) analysis study was performed by Carayol et al. 

to understand the genetic influences on leptin levels and 

identified FAM46A as the negative signaling regulator in 

adipose tissue [25][26]. In addition to that distant enhance 

sequences, LE1 and LepREI, modulate leptin gene expression 

through PPAR gama/ RXRa binding sites. Noncoding RNAs 

and epigenetic factors like DNA methylation found in the 

leptin (ob) and LEP-R genes, are expressions of obesity and 

leptin insensitivity [27][28].  

Mechanisms Underpinning Leptin Resistance: It is worth 

noting that leptin resistance occurs when there is an 

impairment of the effectiveness of the ObRb downstream 

signaling transduction, although in the presence of 

hyperleptinemia, a lack of anti obesity action of leptin 

appears. Therefore, leptin resistance is one of the most 

frequent features in the onset and progression of obesity [29]. 

This condition is very common in obese humans and occurs 

after only few weeks of high fat diet (HFD) in rodents. Since 

the hypothalamus mediates the anti-obesity actions of leptin, 

three mechanisms are currently accepted to mediate central 

leptin resistance, such as the reduction in leptin access to CNS 

through the BBB, the impairment of leptin signaling in first-

order neurons expressing ObRb, or in second-order leptin-

targeted neurons and neural circuits.  

It has been recently suggested that other mechanisms, such 

as the onset of hypothalamic inflammation, autophagy 

deficiency or ER stress, can also mediate the obesity-

associated central leptin resistance. Indeed, since leptin exerts 

its biological effects not only in CNS but also in peripheral 

tissues, parallel to central leptin resistance a peripheral 

dampening in leptin sensitivity can occur. 

Reduction in leptin access to CNS: As it is well-known, 

ObRa, which is highly expressed by capillary cells of the 

choroid plexus, actively transports leptin across the BBB to 

reach the majority of ObRb expressing neurons in the CNS. 

This transport system is saturable and recently it has been 

shown to be flanked by another transport mechanism 

involving the endocytic receptor megalin, as demonstrated by 

a decrease in leptin cerebrospinal fluid (CSF) levels inmegalin 

deficiency [30]. In obese individuals the saturation of leptin 



Singha et al.                                                                                     Leptin: Its Crucial Role in the Fight Against Obesity 

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transport can occur due to the hyperleptinemia, resulting in an 

only slightly increase in the CSF leptin levels [31]. Oh-I et al. 

showed that the impairment of leptin transport across BBB 

can also be caused by the higher plasmatic levels of cytokines  

Figure - The pathophysiology of leptin signaling on its crucial role in regulating appetite and maintaining energy balance [52] 

and fatty acids in obese individuals relative to lean subjects. 

To date, it is still unclear the extent to which the impairment 

of leptin transport to CNS can contribute to the leptin 

resistance. Indeed, leptin can reach the CNS through the 

median eminence, which lacks the BBB. Therefore, ARC first-

order neurons can sense leptin trough their projections into the 

median eminence [32]. 

Impairment of leptin signaling in hypothalamic neurons: 

Leptin resistance can occur by alterations in each component 

of the Ob-Rb downstream signaling cascade. In particular, 

previous findings have highlighted three potential 

mechanisms: a reduced expression of Ob-Rb at plasma 

membrane level, an upregulation of negative regulators of 

leptin signaling, and a downregulation of its positive 

regulators. Diano et al. have demonstrated that Ob-Rb has a 

predominant localization in the Golgi apparatus in 

hypothalamic neuronal and glial cells, thus its trafficking to 

the plasma membrane is necessary to obtain a physiological 

response to leptin stimulation. The Ob-Rb expression pattern 

at cell surface depends on a delicate balance between the 

activity of the Bardet-Biedl syndrome (BBS) proteins, which 

mediate its transport to the plasma membrane, and the rate of 

the ligand independent endocytosis, a process that promotes 

the Ob-Rb internalization. Regarding the second molecular 

mechanism underpinning leptin resistance, the Ob-Rb 

physiological signaling is under control of two negative 

regulators: SOCS-3 and phosphor tyrosine phosphatase (PTP) 

1B [33].  

SOCS3 is involved in the onset of leptin resistance at 

central level, as well as at peripheral level. It has been 

demonstrated that an increase in SOCS3 mRNA expression is 

involved in the development of leptin resistance in skeletal 

muscle from rats on high-fat diet (HFD). Moreover, SOCS3 

inhibits AMPK activation in peripheral metabolically active 

tissues, such the liver, white adipose tissue (WAT) and skeletal 

muscle, contributing to abnormalities of fatty acid 

metabolism. AMPK is a fuel-sensing enzyme, whose activity 

is finely regulated by leptin: in peripheral tissues, i.e. WAT, 

leptin increases its enzyme activity, promoting the catabolic 

pathways toward the fatty acid oxidation and glucose 

internalization, exceeding the anabolism rate.  

On the contrary, leptin inhibits AMPK activity at central 

level, where this enzyme is involved in food intake regulation, 



Singha et al.                                                                                     Leptin: Its Crucial Role in the Fight Against Obesity 

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since it controls the release of hypothalamic neuropeptides. In 

addition to SOCS3, PTP1B is a negative regulator of both 

leptin and insulin signaling. Leptin resistance is also 

associated with a downregulation of positive regulators of Ob-

Rb signal transduction. In particular, the leptin-induced 

STAT3 phosphorylation is essential to obtain a clear activation 

of hypothalamic neurons, releasing thus the anorexigenic 

neuropeptides. 

Impairment of MC4R downstream signal transduction in 

neural circuits: The melanocortin system controls the energy 

balance, especially trough the MC4R, which is mostly 

expressed in the brain. Therefore, alterations in the MCAR-

dependent brain-derived neurotrophic factor 

(BDNF)/Tropomyosin receptor kinase (Trk) B signalling 

pathway, in the ventromedial nucleus (VMN), can affect leptin 

resistance. As demonstrated by Liao et al. [34], mice 

harbouring a truncated long Bdnf 3 UTR develop a severe 

hyperphagia and a clear obese phenotype. In this genetic 

model, leptin is unable to activate hypothalamic neurons and 

reduce food intake. 

Role of hypothalamic ER stress in central leptin 

resistance: The ER is responsible for folding nascent proteins 

and this process is possible until there is a perfect balance 

between the ER capability to fold these macromolecules and 

the amount of loaded proteins. As soon as an imbalance 

between these folding and loading processes occurs, ER stress 

appears, leading to the activation of several pathways (ie. 

unfolded protein response (UPR), inositol-requiring protein 

(IRE)-1 and protein kinase RNA (PKR)-like  kinase (PERK) 

pathways), which collectively attempt to counteract the ER 

stress itself, restoring the ER homeostasis.  

To date, a growing body of evidence has demonstrated the 

involvement of the hypothalamic ER stress in central leptin 

resistance and obesity. Consistently, pharmacological 

approaches, consisting in the central administration of ER 

stress inducers or chemical ER chaperons, are able to 

modulate leptin responsiveness in an opposite manner, 

identifying a role of ER stress in leptin resistance [35]. 

Defective autophagy as a contributor of leptin resistance: 

It has been recently emphasized a key role for the autophagy 

in regulating the overall energy balance, since the inhibition of 

this process, by a neuron- specific deletion of autophagy 

related protein (Atg) 7, can alter the phenotype in mice. In 

particular, mice show an obese phenotype when this well-

known autophagy component is selectively knocked down in 

POMC neurons, probably because this deletion is associated 

also with a reduction of leptin- induced STAT3 

phosphorylation; in agreement with these results, the deletion 

of this gene in AgRP neurons causes a reduction in fat mass 

Collectively, these data highlight that the hypothalamic 

autophagy deficiency is involved in leptin resistance and 

obesity [36]. 

Strategies To Overcome Leptin Resistance:-  

Caloric restriction and exercise: Caloric restriction is the 

first approach for the treatment of obesity able to reduce 

circulating leptin levels, as an alternative to pharmacologic 

reversal of leptin resistance. It has been reported that long 

term exercise, not only decreased leptin levels, but also 

increases the activation of STAT3 and AMPK signalling 

pathways in the hypothalamic arcuate nucleus. Prevention of 

leptin resistance by exercise was also demonstrated by Zhou 

[37], who showed a reduction in hypothalamic SOCS3 mRNA 

expression and JAK2/STAT3 signalling pathway in rats fed a 

high fat diet by exercise. However, when exercise was 

combined with caloric restriction the effect was more evident 

compared to those obtained by exercise or diet approach alone 

[38].  

Reversal of the inhibition of SOCS3 and PTP1B: As 

already depicted, SOCS3 and PTP1B are negative regulator 

proteins of leptin receptor signalling. Therefore their down-

regulation can be considered a useful approach to revert leptin 

resistance [39]. The inhibition of SOCS3 expression and/or 

activity could possibly lead to an interruption of the negative 

feedback loop related to leptin resistance and restore leptin 

activity. Accordingly, ObRb mutation in transgenic mice, 

disabling SOCS3 binding [40]. reduced food intake, increases 

leptin sensitivity and reduced weight gain. Besides SOCS3, 

also PTP1B inhibition seems to be an attractive target to 

overcome lentin resistance [41].  

In fact deletion of PTP1B in mice increases lentin 

sensitivity, reduces body weight and increases energy 

expenditure. These animals also showed an improvement in 

glucose metabolism and uptake, and they were protected by 

DIO. The selective inhibition of PTP1B resulted in dampening 

of STAT3 activation by leptin in HEK cells. To date, inhibitors 

of PTP1B based on capability to bind PTPB1 active site 

(without hydrolysis) have been designed. In particular, 

thiazolidinedione  compounds have been shown to exert anti 

obesity effects as PTP1B inhibitors and PPAR-a activators, 

ameliorating blood lipid profile in mice on high fat diet [42]. 

POMC neuron activation:- Last molecular targets of leptin 

effect on energy balance are POM neurons, therefore their 

activation seems another attractive strategy to overcome leptin 

receptor signal to induce a-MSH-mediated suppression of 

food intake and weight gain together with an increase in 

energy expenditure [43].  

Increase in leptin receptor expression and cell surface 

localization:- An increase in ObR expression and its 

localization at the cell surface are key determinants for cell 

sensitivity to leptin [44]. We demonstrated that in leptin 

resistant ovariectomized obese rats, estradiol replacement 

therapy or long term raloxifene treatment, reduced leptin 

levels and body weight and restored leptin receptor expression 

both in adipose tissue and hypothalamus [45]. Unfortunately, 



Singha et al.                                                                                     Leptin: Its Crucial Role in the Fight Against Obesity 

Online First                                                                                                                      Indian J Pharm Drug Studies | 5  

differently from rodent studies, a recent review of the 

literature regarding estrogen effect on leptin levels in post-

menopausal women, did not show evident beneficial effects 

by hormonal intervention in modulating leptin levels and 

attenuating weight gain. Therefore, the authors discourage the 

hormonal intervention in relation to cardiovascular and 

neoplastic risk associated with the replacement therapy [46]. 

Previously, clinical studies showed an increase in leptin levels 

and body fat content in other studies reported an increase in 

leptin levels in treated woman, not related to change in fat 

mass. It has also been shown that metformin, acting at ObRb 

hypothalamic gene level, is able to increase receptor 

expression and leptin sensitivity, and exert an anorectic effect. 

Moreover, the inverse agonist of cannabinoid receptor 1, 

JD5037,can overcome leptin resistance and reduce weight 

gain [47]. 

Treatment Of Obesity Based On Leptin:-  

Leptin analogous: Metreleptin is a once daily subcutaneously 

administered leptin analogue approved by the FDA in 2014 for 

use in people with leptin deficiency or congenital/acquired 

lipodystrophy, with good clinical results in these conditions. 

Whilst metreleptin monotherapy supports weight loss in obese 

individuals, it is not clinically meaningful with a mean 1.5 kg 

additional weight loss over 24 weeks noted in a previous trial 

[48]. To enhance the effect of leptin analogues, amylin 

mimetics such as pramlintide have been used in combination 

with metreleptin. One study found that use of the 

pramlintide/metreleptin combination resulted in 11.5 kg 

weight loss over 20 weeks compared with 7.4 kg and 7.9 kg 

weight loss respectively in participants receiving either 

metreleptin or pramlintide monotherapy. Unfortunately, the 

development of the combination therapy was discontinued in 

2011 following commercial reassessment [49]. 

Phentermine and topiramate combination therapy: 

Phentermine plus topiramate food intake may be due to an 

increase in hypothalamic CRH, which is an anorexigenic 

neuropeptide [50]. Furthermore, TPM seems to reduce energy 

deposition even in the absence of changes in food intake, 

suggesting a role for TPM in increasing energy expenditure. 

Nonetheless, (TPM) in combination markedly decreased body 

weight in overweight and obese patients and the US. Food and 

Drug Administration just recommended this drug to be approved 

to treat obesity TPM treatment has been shown to reduce 

adiposity in humans and rodents. This reduction in adiposity is 

related to decreased food intake and reduced body fat gain. In 

rodents, the TPM treatment induced reduction in the 

molecular mechanisms by which TPM- induced weight loss 

occurs are contradictory and remain to be clarified [51]. 

CONCLUSION 

Obesity is a global health concern till date, it having such 

strong epidemiological evidences which link it to various 

other health issues. Genetic factors like mutation in leptin 

signaling plays an important role in obesity. This influences 

both somatic and hereditary genomic events. Activation of 

specific pathways due to metabolic shift which is associated 

with obesity and tumor progression is contributed by these 

genetic factors along with the gut microbiome. 

Comprehensive approaches are required to examine leptin’s 

role in obesity can be done by metagenomics, 

metatranscriptomics, metaproteomics and metabolomic 

studies. Further research should be targeted on the biology of 

the leptin focusing more on the acquired genetic variations 

and understand more about there interaction with the gut 

microbiome. Longitudinal studies focusing on unveiling these 

factors from early life to adulthood may contribute to future 

research in building critical preventive strategies, potentially 

leading to innovative treatments and managing obesity in a 

better way.    

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How to cite this article: Singha S, Nayak S, Bishayee R, 

Sarkar P, Ghosh P, Dutta U, Mishra P. Decoding Leptin: 

Unraveling the Role of Leptin Signaling in the Battle against 

Obesity. Indian J Pharm Drug Studies. 2024; Online First. 

Funding: None;                 Conflicts of Interest: None Stated 

 

 

 

https://doi.org/10.1210/mend.16.4.0800
https://doi.org/10.1152/ajpregu.1998.274.1.R204
https://doi.org/10.1210/jcem.86.2.7245
https://doi.org/10.3389/fendo.2021.585887

