Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity
Abstract
1. Introduction
2. Materials and Methods
3. Discussion
3.1. Mechanisms of Energy Expenditure
3.2. Thrifty Gene Hypothesis
3.3. Set Point Theory
3.4. Melanocortin System and Hypothalamic Regulation
3.5. Metabolic Memory
3.6. Adipose Tissue Dysfunction
3.7. White, Brown, and Beige Adipose Tissue
3.8. Microbiome
3.9. Lifestyle Interventions
3.10. Pharmacological Interventions
4. Bariatric Surgery
5. Summary and Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
NCDs | Noncommunicable Diseases |
WHO | World Health Organization |
CVDs | Cardiovascular Diseases |
BMR | Basal Metabolic Rate |
TEF | Thermic Effect of Food |
TEA | Thermic Effect of Activity |
FFM | Fat-free Mass |
LBM | Lean Body Mass |
MAPK | Mitogen-Activated Protein Kinase |
TGF-β | Transforming Growth Factor Beta |
T2DM | Type 2 Diabetes Mellitus |
POMC | Pro-opiomelanocortin |
CART | Cocaine- and Amphetamine- Regulated Transcript |
AgRP | Agouti-related Peptide |
NPY | Neuropeptide Y |
α-MSH | α-Melanocyte Stimulating Hormone |
MC4R | Melanocortin-4 Receptor |
DCCT | Diabetes Control and Complications Trial |
CpG | Cytosine linked by a phosphate to guanine |
CGIs | CpG Islands |
DMRs | Differentially Methylated Regions |
TFs | Transcription factors |
PPARγ | Peroxisome Proliferator-Activated Receptor Gamma |
miRNAs | microRNAs |
WHR | Waist-to-Hip |
WAT | White Adipose Tissue |
BAT | Brown Adipose Tissue |
BeAT | Beige Adipose Tissue |
UCP1 | Uncoupling Protein 1 |
ATP | Adenosine Triphosphate |
CR | Calorie Restriction |
β3-AR | β3-Adrenergic Receptor |
GLP-1RA | Glucagon-like Peptide 1 Receptor Agonists |
FDA | Food and Drug Administration |
GIP | Glucose-Dependent Insulinotropic Polypeptide |
NMDA | N-methyl-D-aspartate |
LPS | Lipopolysaccharide |
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Main Mechanisms | Pathways | Description |
---|---|---|
Decreased energy expenditure | Sedentary lifestyle | Reduced thermic effect of activity |
High-calorie diet (processed foods) | Increased calorie intake | |
BMR alteration (disadvantageous muscle/fat ratio) | Lower basal metabolic rate | |
Genetic predisposition | Thrifty gene | Increased fat accumulation and reduced energy expenditure |
Genetic drift | Removal of natural selection allowed more diverse genetic variations | |
Cerebral set range theory | Hypothalamic pathway | Through neuroendocrine regulation, the body aims to achieve the set weight range |
Appetite regulation | Through endocrine mechanisms, the calorie intake is increased | |
Decreased energy expenditure | Lower basal metabolic rate | |
Neuroendocrine regulation | POMC | When cleaved, α-MSH is produced, which is an agonist of MC4R, thus increasing satiety and energy expenditure |
AgRP | An inverse agonist of MC4R, decreases satiety and energy expenditure | |
NPY | Through the inhibition of POMC neurons they decrease satiety and energy expenditure | |
MC4R | Activation through agonists shifts the metabolism to anorexigenic state, while inverse agonists cause orexigenic state. | |
Metabolic memory/epigenetic alterations | DNA methylation alterations | Hypomethylation of obesity-related genes has been found in obese patients |
Histone modifications | Histone deacetylation via histone deacetylases promotes inflammation and attenuate insulin sensitivity | |
miRNA regulation | The dysregulation of miRNA function leads to adipocyte hypertrophy and impaired lipid metabolism | |
Adipose tissue dysfunction | Increased inflammation | Hypertrophied adipocytes promote inflammation, leading to insulin and leptin resistance |
Altered adipokine secretion | Increased levels of pro-inflammatory, decreased levels of anti-inflammatory adipokines | |
Disrupted satiety-signaling | Leptin resistance can lead to decreased satiety and increased calorie intake | |
Composition of adipose tissue | Brown and beige adipocytes | Bifunctional adipocytes capable not only of energy storage, but also heat production |
UCP1 | Allows uncoupled respiration for the adipocytes, thus increasing energy expenditure | |
Microbiome | Increased ratio of Firmicutes bacteria | May increases the host’s energy uptake |
Elevated number of Bacteroidetes | Increased LPS in the circulation, further decreasing insulin sensitivity |
Drug Class | Example | Approved for Obesity? | Weight Loss Effect |
---|---|---|---|
Biguanides | Metformin | No | Subtle |
β3-AR agonists | Mirabegron | No | Subtle |
SGLT2 inhibitors | Canagliflozin | No | Moderate |
Opioid antagonist/Dopamine reuptake inhibitor | Naltrexone/bupropion | Yes | Moderate |
GLP-1RA | Liraglutide | Yes | Substantial |
GLP-1/GIP dual agonists | Tirzepatide | Yes | Substantial |
NMDA antagonist/GLP-1RA | Not available | Not available | Substantial |
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Szekeres, Z.; Szabados, E.; Pálfi, A. Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity. Biomedicines 2025, 13, 1989. https://doi.org/10.3390/biomedicines13081989
Szekeres Z, Szabados E, Pálfi A. Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity. Biomedicines. 2025; 13(8):1989. https://doi.org/10.3390/biomedicines13081989
Chicago/Turabian StyleSzekeres, Zsolt, Eszter Szabados, and Anita Pálfi. 2025. "Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity" Biomedicines 13, no. 8: 1989. https://doi.org/10.3390/biomedicines13081989
APA StyleSzekeres, Z., Szabados, E., & Pálfi, A. (2025). Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity. Biomedicines, 13(8), 1989. https://doi.org/10.3390/biomedicines13081989