Terungkap! Biang Kerok Obesitas Ada di Leptin Resistance—Inilah Jalur Molekuler dan Terapi Barunya!

Leptin Resistance and Its Molecular Pathways: Genetic Variations and Therapeutic Prospects in Obesity Management

 Pudjiatmoko

Member of the Nanotechnology Technical Committee, National Standardization Agency, Indonesia

ABSTRACT

Background: Leptin, an adipocyte-derived hormone, regulates appetite and energy expenditure through hypothalamic signaling. Although circulating leptin levels are elevated in obesity, its physiological effects are markedly diminished—a condition known as leptin resistance.

Objective: This review aims to elucidate the molecular mechanisms of leptin signaling, the impact of genetic variations in the leptin (LEP) and leptin receptor (LEPR) genes, and recent therapeutic advances designed to restore leptin sensitivity.

Results: Dysregulation of leptin signaling involves impaired JAK2–STAT3 activation, upregulation of SOCS3, endoplasmic reticulum stress, and interference from inflammatory cytokines. Genetic polymorphisms in LEP and LEPR contribute to interindividual differences in obesity susceptibility. Emerging therapies include pharmacological chaperones, leptin sensitizers, and gene-based approaches.

Conclusion: Understanding the molecular mechanisms underlying leptin resistance offers promising avenues for precision-based obesity management.

Keywords: leptin resistance; obesity; leptin signaling; leptin receptor; genetic polymorphism; metabolic regulation; targeted therapy

 

1. INTRODUCTION

Obesity has become a major global health concern, contributing to increased morbidity and mortality through its association with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome (1). Among the hormones regulating energy homeostasis, leptin—encoded by the ob gene—plays a central role in linking adipose tissue mass with central nervous system control of energy expenditure and food intake (2).

 

Under normal physiological conditions, leptin acts on hypothalamic neurons to suppress appetite and increase thermogenesis. However, in most obese individuals, elevated circulating leptin levels fail to elicit the expected physiological effects, a condition referred to as leptin resistance (3).

This manuscript reviews the leptin signaling cascade, explores genetic variations affecting leptin and its receptor, and summarizes novel therapeutic strategies aimed at improving leptin responsiveness.

 

2. MATERIALS AND METHODS

This narrative review was conducted through a systematic literature search in PubMed, Scopus, and Web of Science databases from 2000 to 2025 using the keywords: “leptin resistance,” “LEPR polymorphism,” “leptin signaling,” “obesity therapy,” and “leptin sensitizer.” Original articles, systematic reviews, and meta-analyses written in English were included. Studies focusing on animal or human models of leptin resistance were prioritized. Data were extracted on the molecular mechanisms of leptin signaling, identified polymorphisms, and experimental or clinical interventions targeting leptin sensitivity.

 

3. RESULTS

3.1 Leptin Signaling Pathways

Leptin exerts its biological effects by binding to the leptin receptor (LEPR), a class I cytokine receptor primarily expressed in hypothalamic neurons (4). The long isoform, Ob-Rb, activates intracellular signaling through the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathways (5). Activated STAT3 regulates the expression of POMC, NPY, and AgRP genes, orchestrating satiety and energy homeostasis (Figure 1).

Figure 1. Diagram of leptin signaling pathway through JAK2–STAT3, SOCS3, and ER stress interactions.

 

3.2 Mechanisms Underlying Leptin Resistance

Multiple cellular and molecular processes contribute to leptin resistance, including:

1. SOCS3 overexpression, which inhibits JAK2 phosphorylation;
2. Endoplasmic reticulum (ER) stress, impairing receptor folding and trafficking;
3. Inflammatory cytokines such as TNF-α and IL-6, which disrupt hypothalamic leptin signaling; and
4. Reduced leptin transport across the blood–brain barrier (BBB) (6–9).

These mechanisms create a chronic state of central leptin resistance, leading to sustained hyperphagia and positive energy balance.

 

3.3 Genetic Polymorphisms in LEP and LEPR

Genetic variability in LEP and LEPR genes influences leptin secretion, receptor affinity, and downstream signal transduction efficiency (10). The LEP G-2548A polymorphism in the promoter region enhances transcriptional activity, resulting in higher leptin levels in obese individuals (11).

In contrast, LEPR variants such as Q223R (rs1137101) and K656N (rs8179183) modify receptor conformation, decreasing leptin binding capacity and signal transduction efficiency (12–14).

Population-based studies have associated these polymorphisms with variations in body mass index (BMI), insulin resistance, and lipid metabolism (15,16). Ethnic and sex-specific differences further highlight gene–environment interactions influencing obesity risk.

Table 1. Summary of major LEP and LEPR polymorphisms and their metabolic associations.

3.4 Therapeutic Strategies to Overcome Leptin Resistance

3.4.1 Pharmacological Modulation

Agents targeting hypothalamic inflammation and ER stress—such as chemical chaperones (4-phenylbutyrate) and salicylates—have been shown to restore leptin sensitivity in preclinical models (17).

3.4.2 Leptin Sensitizers and Combination Therapy

Combination regimens pairing leptin with amylin analogs (pramlintide) or GLP-1 receptor agonists (liraglutide) have demonstrated synergistic effects in enhancing satiety and promoting weight loss (18,19).

3.4.3 Genetic and Molecular Interventions

Novel approaches include CRISPR/Cas9-mediated correction of LEPR mutations and RNA-based therapies targeting negative regulators such as SOCS3 and PTP1B (20). While these strategies hold great promise, further research is needed to validate their safety, efficacy, and translational potential.

 

4. DISCUSSION

This review highlights the complexity of leptin resistance, which arises from the interplay between molecular, genetic, and environmental factors. Chronic inflammation and ER stress disrupt leptin signaling at multiple levels, while genetic polymorphisms in LEP and LEPR further modulate individual susceptibility.

 

Therapeutic innovations targeting leptin sensitivity—particularly through combination therapy and gene-based interventions—represent a paradigm shift in obesity management. Nevertheless, the translation of these findings into clinical practice requires long-term studies addressing pharmacokinetics, safety profiles, and personalized response prediction.

 

Future research integrating multi-omics analysis, systems biology, and computational modeling may accelerate the development of precision medicine approaches to overcome leptin resistance and improve metabolic outcomes.

 

5. CONCLUSION

Leptin resistance remains a fundamental challenge in obesity therapy. A deeper understanding of the molecular pathways, genetic determinants, and signaling modulators of leptin action is essential for designing targeted and individualized interventions. Bridging the gap between experimental findings and clinical application will be critical to achieving sustainable metabolic health outcomes.

 

Acknowledgments

The author gratefully acknowledge contributions from colleagues and researchers whose work has advanced the understanding of leptin biology and metabolic regulation.

 

Conflict of Interest Statement

The author declare no conflict of interest related to this study.

 

REFERENCES

1. World Health Organization. Obesity and overweight. WHO Fact Sheet. 2023.
2. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–432.
3. Myers MG Jr, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537–556.
4. Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab. 2019;1:754–764.
5. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, et al. STAT3 signaling is required for leptin regulation of energy balance. Cell Metab. 2003;1(1):65–75.
6. Hosoi T, Ozawa K. Leptin signaling and endoplasmic reticulum stress. Biochimie. 2010;92(6):626–631.
7. Wisse BE, Schwartz MW. Role of cytokine signaling in the regulation of energy balance: lessons from leptin and insulin. J Clin Endocrinol Metab. 2003;88(10):4548–4555.
8. Banks WA. The blood–brain barrier and the regulation of leptin access to the brain. Endocrinology. 2008;149(12):6251–6255.
9. Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab. 2006;17(9):365–371.
10. Considine RV, et al. Serum leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292–295.
11. Le Stunff C, et al. A common promoter variant of the leptin gene associated with obesity. J Clin Endocrinol Metab. 2000;85(5):1690–1694.
12. Quinton ND, et al. LEPR polymorphisms and obesity risk. Diabetes. 2001;50(9):2153–2158.
13. Mammes O, et al. Association of LEPR Q223R polymorphism with obesity. Int J Obes. 2001;25(2):200–204.
14. Chagnon YC, et al. Leptin receptor variants and obesity. Obes Res. 2000;8(6):672–679.
15. Paracchini V, et al. LEPR polymorphisms and metabolic outcomes in diverse populations. J Mol Endocrinol. 2005;34(3):795–803.
16. Zhang X, et al. Ethnic and sex-specific associations of LEPR variants with obesity. Metabolism. 2014;63(4):530–539.
17. Ozcan U, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis. Science. 2006;313(5790):1137–1140.
18. Ravussin E, et al. Combined amylin/leptin therapy in obese individuals. Proc Natl Acad Sci USA. 2009;106(40):16713–16718.
19. Astrup A, et al. GLP-1 receptor agonists and weight management. Lancet Diabetes Endocrinol. 2019;7(8):649–659.
20. Güler MA, et al. Gene editing and RNA therapeutics in obesity. Trends Mol Med. 2022;28(7):573–589.

#leptinresistance 

#obesitas 

#geneticleptin 

#metabolismemolekuler 

#terapiobesitas