Advancing Obesity Therapeutics: From Single-Target to Multi-Target Drug Development

Hidden Risks of Obesity: Weight Management for Optimal Health

Obesity has emerged as a critical global health challenge, driven by shifts in lifestyle and dietary patterns. Beyond its impact on physical appearance, obesity is a major risk factor for diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, and mental health conditions. It also imposes significant strain on public healthcare systems. This multifaceted crisis underscores the urgent need for deeper research into obesity’s etiology and regulatory mechanisms to develop evidence-based prevention strategies and therapeutic interventions for associated comorbidities.

https://www.bmisurgery.com/health-risks-tied-to-obesity-2

Health risks tied to obesity – body mass index

Mechanisms of Obesity: From Energy Imbalance to Multidimensional Metabolic Dysregulation

Obesity pathogenesis involves complex interactions among energy metabolism dysregulation, adipose tissue dysfunction, and chronic inflammation. Central to this is a persistent energy surplus, leading to pathological expansion of white adipose tissue (hyperplasia/hypertrophy) and impaired thermogenic capacity of brown adipose.

https://doi.org/10.1038/s41392-022-01149-x

Signaling pathways involved in pro-obesity and anti-obesity mechanisms

Excessive adipocyte accumulation triggers endocrine dysregulation characterized by abnormal secretion of adipokines including leptin, adiponectin, and resistin. Leptin resistance manifests through defective hypothalamic JAK2/STAT3 signaling that disrupts appetite regulation, while diminished adiponectin levels impair AMPK/PGC-1α pathway-mediated fatty acid oxidation. Chronic inflammation constitutes a pivotal mechanism where macrophage infiltration in adipose tissue activates TLR4/NF-κB signaling to release pro-inflammatory cytokines (TNF-α, IL-6), subsequently stimulating JNK and IKKβ signaling nodes. This cascade induces serine phosphorylation of insulin receptor substrate 1, thereby impairing PI3K/Akt insulin signaling and promoting systemic insulin resistance. Concurrently, nutrient overload activates mTORC1 signaling to enhance lipid synthesis via SREBP-1c while suppressing autophagy. These cascading abnormalities within signaling networks establish a vicious cycle of metabolic dysregulation, ultimately culminating in complications such as type 2 diabetes and cardiovascular diseases.

Obesity Therapeutics: The Rise of Multi-Target Synergy

- GLP-1R Agonists: Pioneering Single- to Multi-Target Strategies

GLP-1R agonists dominate the weight management therapeutic landscape. NovoNordisk's semaglutide (WegovyTM), a single-target GLP-1R agonist, demonstrates 15% weight reduction over a 68-week treatment period, achieving over 7 billion in sales in 2023. EliLilly's tirzepatide (MounjarorTM), a dual GLP-1R/GIPR agonist, demonstrated superior efficacy with 22.510 billion. Lilly's retatrutide, a novel triple agonist targeting GLP-1R/GlPR/GCGR receptors, achieved 24% weight reduction in Phase l studies and is anticipated to become the first FDA-approved triple-target weight loss medication by 2025.

https://doi.org/10.1038/s41392-022-01149-x

GLP-1 signaling pathway in obesity pathogenesis

- Emerging Targets: Unlocking New Horizons in Obesity Therapeutics

The full-length G protein-coupled receptor 75 (GPR75), a hypothalamus-specific GPCR, exerts dual regulatory control over appetite and energy homeostasis via CCL5/RANTES-mediated activation. Upon ligand binding, GPR75 couples with heterotrimeric G-proteins to trigger inositol trisphosphate/calcium signaling cascades, modulating activity in NPY/AGRP/GABA co-expressing neurons critical for metabolic balance. A landmark science study revealed that individuals harboring GPR75 truncating mutations exhibit a 1.8 kg/m² reduction in BMI and 54% lower obesity risk. Preclinical validation demonstrated that genetic knockout confers resistance to high-fat diet-induced obesity and enhances glucose metabolism, underscoring GPR75's dual mechanistic role—simultaneously suppressing hyperphagia and optimizing energy expenditure—as a novel anti-obesity therapeutic target with transformative translational potential.

https://doi.org/10.1002/oby.23692

GPR75 knockout mice exhibit reduced food intake under high-fat diet conditions

Bimagrumab, a fully human monoclonal antibody developed by Eli Lilly, selectively targets activin type II receptors (ActRIIA/B) to block signaling pathways mediated by activins and myostatin. By inhibiting Smad2/3 phosphorylation, it reduces myostatin-mediated protein degradation, thereby enhancing fat metabolism and increasing lean muscle mass. Preclinical and Phase II clinical trials demonstrated its dual efficacy: a 12.3% increase in muscle volume alongside significant body recomposition (lean body mass +8.5%, fat mass -6.2%). This novel mechanism positions Bimagrumab as a potential first-in-class therapeutic to address the unmet need in muscle-metabolism combination therapies, offering transformative potential for obesity and sarcopenia management.

https://doi.org/10.1016/j.cytogfr.2021.04.001

A map of the activin receptor signaling pathway as we currently know it in skeletal muscle

A member of the TGF-β superfamily, GDF-15 suppresses appetite and reduces food intake through binding to the hindbrain-specific receptor GFRAL and activating RET kinase signaling—a pathway distinct from traditional appetite-regulatory systems involving leptin or ghrelin. Human genetic studies corroborate the GDF15-GFRAL axis's association with obesity, while its anti-inflammatory effects, mediated via mechanisms not yet fully elucidated, broaden its therapeutic potential in metabolic diseases. Leveraging its unique dual mechanisms—appetite suppression and inflammatory modulation—GDF-15 emerges as a novel therapeutic target for obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cancer cachexia. This multifaceted action positions GDF-15-based therapies to transcend limitations of conventional approaches, offering a paradigm shift in managing complex metabolic-inflammatory comorbidities.

https:/doi.orgy10.1016/j.tem.2020.10.004

GDF15 as a signal in the organism

FGF-21, a hepatic secretory hormone central to metabolic regulation, has emerged as a core biomarker for obesity, with serum levels positively correlated with BMI and visceral adiposity. These levels dynamically reflect both the severity of obesity and therapeutic weight-loss efficacy. Mechanistically, FGF-21 orchestrates dual metabolic modulation by suppressing appetite through hypothalamic signaling while activating adipose tissue thermogenesis and white adipose browning, thereby synergizing "reduced caloric intake + enhanced energy expenditure." Additionally, it demonstrates significant therapeutic benefits in ameliorating insulin resistance, hyperglycemia, and dyslipidemia. Preclinical studies underscore the therapeutic promise of recombinant FGF-21 analogs, which achieve 10%-15% body weight reduction in animal models and comprehensively reverse metabolic dysregulation. These findings position FGF-21-based therapies as transformative candidates for addressing multifactorial obesity-related pathologies.

https://doi.org/10.3389/fphar.2022.1089214

FGF21 resistance, the potential mechanism leading to metabolic diseases

ACROBiosystems Advances Obesity Therapeutics Through Novel Solutions

We have developed a comprehensive portfolio of recombinant proteins and functional cell lines targeting key receptors in weight management pathophysiology, including GLP-1R, GCGR, GIPR, GPR75, GDF-15, FGF-21, and Activin R. These innovative solutions provide robust support for advancing targeted therapeutic development in obesity treatment, enabling researchers to accelerate the discovery and optimization of precision medicines and intervention strategies for metabolic disorders.

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Reference

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3. Chen, Zhiwei, et al. "The potential function and clinical application of FGF21 in metabolic diseases." Frontiers in pharmacology 13 (2022): 1089214. https://doi.org/10.3389/fphar.2022.1089214

4. Lodberg, Andreas. "Principles of the activin receptor signaling pathway and its inhibition." Cytokine & Growth Factor Reviews 60 (2021): 1-17. https://doi.org/10.1016/j.cytogfr.2021.04.001

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6. Rochette, Luc, et al. "Insights into mechanisms of GDF15 and receptor GFRAL: therapeutic targets." Trends in Endocrinology & Metabolism 31.12 (2020): 939-951. https:/doi.orgy10.1016/j.tem.2020.10.004