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Review
. 2025 Jul 11:e13978.
doi: 10.1111/obr.13978. Online ahead of print.

The Genetic Blueprint of Obesity: From Pathogenesis to Novel Therapies

Gašper Tonin  1 , Stjepan Eržen  2 , Zala Mlinarič  1   3 , Dubravka Jurišić Eržen  2   4 , Simon Horvat  5 , Tanja Kunej  5 , Jasna Klen  6   7
Affiliations
Review

The Genetic Blueprint of Obesity: From Pathogenesis to Novel Therapies

Gašper Tonin et al. Obes Rev. .

Abstract

Obesity is a chronic metabolic disease characterized by disturbances in energy homeostasis, leading to excessive fat accumulation. The pathogenesis of the disease is shaped by a complex interplay of genetic, epigenetic, biological, psychological, and environmental factors. These contributors affect regulatory mechanisms in the hypothalamus, hormonal signaling, and the gut-brain axis, all of which control energy intake, expenditure, and energy utilization in body tissues. In this context, particular attention is given to the role of genetic factors, which have a major impact on an individual's susceptibility to disease and support the development of personalized preventive and therapeutic approaches. Modern obesity treatment goes beyond weight reduction and focuses on optimizing body composition by reducing fat mass and increasing lean mass. This review includes a detailed overview of the mechanisms and clinical effects of current pharmacological approaches to obesity treatment, alongside other established strategies such as lifestyle modifications and bariatric surgery. It specifically discusses lipase inhibitors, opioid antagonists, sympathomimetics, and GLP-1 receptor agonists. Looking ahead, emerging therapies-such as microbiota modulation, dual and triple drug combinations, PYY agonists, and monoclonal antibodies-are expected to play a crucial role in the management of obesity. Furthermore, this review explores the potential of CRISPR-based technology for monogenic obesity, opening new avenues for targeted obesity treatments and identifying promising research directions. In the time to come, personalized medicine might have a fundamental place in the management of obesity, providing tailored and more effective therapeutic approaches that prioritize the long-term improvement of body composition and health outcomes in patients.

Keywords: CRISPR/Cas9; dual therapy; energy homeostasis; gene therapy; gut–brain axis; microbiota; personalized medicine.

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