The Genetic Blueprint of Obesity: From Pathogenesis to Novel Therapies

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.

FIGURE 1

Obesity is a major risk factor for a wide range of comorbid conditions affecting multiple organ systems. It is frequently associated with diseases such as type 2 diabetes mellitus, cardiovascular disease, non‐alcoholic fatty liver disease, obstructive sleep apnea, and certain cancers, which collectively contribute to increased morbidity and mortality in individuals with obesity. GERD—gastroesophageal reflux disease; NAFLD—non‐alcoholic fatty liver disease.

FIGURE 2

An integrated overview of discussed topics, illustrating obesity's multifactorial etiology, pathogenesis, associated comorbidities, and evolving treatment landscape. Etiological factors include environmental, behavioral, psychological, genetic, and epigenetic influences, which interact to disrupt gut‐brain communication and central and peripheral regulatory mechanisms, ultimately leading to adipose tissue accumulation. The downstream health consequences are associated with metabolic, cardiovascular, renal, respiratory, reproductive, gastrointestinal, oncological, and psychological domains. Current therapeutic strategies encompass lifestyle interventions, pharmacological agents such as GLP‐1 receptor agonists, and surgical bariatric procedures. Emerging treatments include microbiota modulation, dual and triple pharmacotherapy, PYY agonists, monoclonal antibodies, and gene‐editing technologies. GLP‐1RA—glucagon‐like peptide‐1 receptor agonist; ESG—endoscopic sleeve gastroplasty; RYGB—Roux‐en‐Y gastric bypass; OAGB—one‐anastomosis gastric bypass; GERD—gastroesophageal reflux disease; NAFLD—non‐alcoholic fatty liver disease; CKD—chronic kidney disease; OSA—obstructive sleep apnea; PCOS—polycystic ovary syndrome; PYY—peptide YY; AAV—adeno‐associated virus; CRISPR—clustered regularly interspaced short palindromic repeats; Cas9—CRISPR‐associated protein 9; CRISPR/Cas9—CRISPR‐associated system used for gene editing; CRISPRi—CRISPR interference; CRISPRa—CRISPR activation.

FIGURE 3

The interplay of different factors regulating body weight and body composition. Kcal—kilocalories; RMR—resting metabolic rate; DEE—diet‐induced energy expenditure; AEE—activity‐induced energy expenditure.

FIGURE 4

Etiological model of obesity illustrating the multifactorial interactions among biological, environmental, behavioral, and psychological factors. These influences disrupt energy homeostasis—defined as the balance between energy intake and expenditure—thereby promoting adipose tissue accumulation and the development of obesity. TEF—thermic effect of food; RMR—resting metabolic rate.

FIGURE 5

Genetic architecture of obesity illustrating key gene loci associated with specific obesity‐related traits. Distinct sets of genes are linked to visceral fat accumulation, body fat accumulation, BMI, waist‐to‐hip ratio, waist circumference, and birth weight, each contributing to the overall risk and development of obesity. LYPLAL1—lysophospholipase‐like 1; THNSL2—threonine synthase‐like 2; LCORL—ligand dependent nuclear receptor corepressor‐like; HMGA2—high mobility group AT‐hook 2; ADCY5—adenylate cyclase 5; NTRK2—neurotrophic receptor tyrosine kinase 2; ADRB1—adrenoceptor beta 1; CDKAL1—CDKAL1 threonylcarbamoyladenosine tRNA methylthiotransferase (previously CDK5 regulatory subunit associated protein 1‐like 1); COBLL1—cordon‐bleu WH2 repeat protein like 1; NRXN3—neurexin 3; SLC22A18—solute carrier family 22 member 18; NEGR1—neuronal growth regulator 1; BDNF—brain‐derived neurotrophic factor; FTO—fat mass and obesity‐associated protein; MC4R—melanocortin 4 receptor; TMEM18—transmembrane protein 18; SEC16B—SEC16 homolog B; IRS1—insulin receptor substrate 1; TOMM40—translocase of outer mitochondrial membrane 40; CRTC1—CREB regulated transcription coactivator 1; CTSS—cathepsin S; PAX5—paired box 5; IGF2BP1—insulin‐like growth factor 2 mRNA‐binding protein 1; MSRA—methionine sulfoxide reductase A; TSC22D2—TSC22 domain family member 2; TFAP2B—transcription factor AP‐2 beta; RREB1—Ras‐responsive element binding protein 1; STAB1—stabilin 1; CEP120—centrosomal protein 120; NCAM2—neural cell adhesion molecule 2.

FIGURE 6

Novel therapeutic approaches for obesity treatment. IL‐6—interleukin‐6; TNF—tumor necrosis factor; SCFAs—short‐chain fatty acids; PYY—peptide yy; GLP‐1—glucagon‐like peptide‐1; GIP—gastric inhibitory peptide; PYY3–36—peptide yy3–36; TALEN—transcription activator‐like effector nuclease; CRISPR—clustered regularly interspaced short palindromic repeats.

FIGURE 7

CRISPR‐based approaches to obesity treatment. Currently, studies are still being conducted on animal models and human cells in vitro. Different delivery vectors (adenoviruses, non‐viral vectors, and physical methods) are used in these models. The lower part of the figure explains the basic approaches to genome editing with CRISPR technology, including gene knockout, down‐regulation, up‐regulation, and gene addition or repair. Key target genes involved in metabolism, fat storage, and thermogenesis are listed, along with corresponding research references. CRISPR—Clustered Regularly Interspaced Short Palindromic Repeats; CRISPRi—CRISPR interference; CRISPRa—CRISPR activation; AAV—adeno‐associated viruses; Nrip1—nuclear receptor‐interacting protein 1; IKKβ—an inhibitor of nuclear factor kappa‐B kinase subunit beta; Irx3—Iroquois homeobox 3; Fabp4—fatty acid‐binding protein 4; Bcl2—B‐cell lymphoma 2; Sim1—single‐minded 1; Fgf21—fibroblast growth factor 21; Fndc5—fibronectin type III domain‐containing protein 5; UCP1—uncoupling protein 1; LEP—leptin; MC4R—melanocortin 4 receptor.