Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction
Abstract
1. Introduction
2. Pathophysiological Insights into Obesity-Driven Metabolic Disorder
2.1. Type II Diabetes Mellitus (T2DM)
2.1.1. Overview of T2DM
2.1.2. Mitochondrial Dysfunction in T2DM Pathogenesis
2.1.3. The Role of Chronic Inflammation in T2DM
2.1.4. Therapeutic Implications
Drug | Mechanism & Molecular Target | Developer | ClinicalTrials.gov Identifier | Phase | References |
---|---|---|---|---|---|
Imeglimin | Oral Glimin class; enhances mitochondrial function | Poxel & Sumitomo Dainippon; approved by Japan’s PMDA in 2021 as Twymeeg®. Approval was based on Phase 3 trials in Japan. In U.S., only Phase II trials has been completed. | N/A | 2 (FDA) | [99,100] |
MSDC-0602K | Azemiglita zone; MPC inhibitor; PPARγ-sparing insulin sensitizer targeting mitochondrial pyruvate carrier (mTOT) | Cirius Therapeutics (Metabolic Solutions) | NCT02784444 (EMMINECE), NCT03970031 (planned) | 3 | [101] |
BGP-15 | HSP modulator; orally active co-inducer of heat shock proteins (HSP72); reduces oxidative and ER stress | N-Gene/Mitochon (HU) | NCT01069965 | 2a | [102] |
HU6 | Mitochondrial uncoupler | Rivus Pharmaceuticals (Phase 2b in obesity+T2DM ongoing) | NCT04874233 | 2b | [103] |
Pegbelfermin | FGF21 analog; enhances lipid oxidation, weight loss, and insulin-independent glucose uptake | Bristol Myers Squibb (BMS-986036) | NCT02071509 | 2a | [104] |
SS-31 (Elamipretide) | Selectively binds to Cardiolipin in inner mitochondrial membrane, stabilizing mitochondrial structure and function | Stealth Bio Therapeutics (developing for Barth syndrome) | N/A (Preclinical Studies Only) | N/A | [94] |
2.2. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
2.2.1. Overview of MASLD
2.2.2. Mitochondrial Dysfunction in MASLD Progression
2.2.3. Hepatic Inflammation in MASLD
2.2.4. Therapeutic Implications
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACOX1 | Acyl-CoA oxidase 1 |
ACSL1 | Acyl-CoA synthetase long-chain family member 1 |
ACSL5 | Acyl-CoA synthetase long-chain family member 5 |
AMPK | AMP-activated protein kinase |
BAT | Brown adipose tissue |
BAX | BCL2-associated X protein |
BGP-15 | Hydroximic acid derivative BGP-15 |
BMI | Body mass index |
CACT | Carnitine-acylcarnitine translocase |
CARD | Caspase recruitment domain |
CCL2 | C-C motif chemokine ligand 2 |
cf-mtDNA | Cell-free mitochondrial DNA |
CMPK2 | Cytidine/uridine monophosphate kinase 2 |
CPT1A | Carnitine palmitoyltransferase 1A |
CPT2 | Carnitine palmitoyltransferase 2 |
CRID3 | Cytokine release inhibitory drug 3 |
CRP | C-reactive protein |
CS | Citrate synthase |
CVOT | Cardiovascular outcome trial |
DAG | Diacylglycerol |
DAMPs | Damage-associated molecular patterns |
Δψm | Mitochondrial membrane potential |
ETC | Electron transport chain |
ETF | Electron transfer flavoprotein |
ETFDH | Electron transfer flavoprotein dehydrogenase |
FABP1 | Fatty acid-binding protein 1 |
FAO | Fatty acid β-oxidation |
FFAs | Free fatty acids |
FGF21 | Fibroblast growth factor 21 |
GAS | Gastrocnemius |
GCN2 | General control nonderepressible 2 |
GSIS | Glucose-stimulated insulin secretion |
GSDMD | Gasdermin D |
HCC | Hepatocellular carcinoma |
HFD | High-fat diet |
HIF | Hypoxia-inducible factor |
HOMA-β | Homeostatic model assessment of β-cell function |
HSP | Heat shock protein |
IL | Interleukin |
IP3R | Inositol 1,4,5-trisphosphate receptor |
IRS | Insulin receptor substrate |
JAK | Janus kinase |
JNK | c-Jun N-terminal kinase |
LPS | Lipopolysaccharide |
MAMs | Mitochondria-associated membranes |
MASLD | Metabolic dysfunction-associated steatotic liver disease |
MASH | Metabolic dysfunction-associated steatohepatitis |
MCC950 | NLRP3 inflammasome inhibitor MCC950 |
MCL-1 | Myeloid cell leukemia 1 |
MetALD | Metabolic dysfunction-associated alcohol-related liver disease |
MLKL | Mixed lineage kinase domain-like protein |
MPC | Mitochondrial pyruvate carrier |
mPTP | Mitochondrial permeability transition pore |
mtDNA | Mitochondrial DNA |
mtDAMPs | Mitochondrial damage-associated molecular patterns |
mTOT | Mitochondrial target of thiazolidinediones |
NAFLD | Non-alcoholic fatty liver disease |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NK | Natural killer |
NLRP3 | NOD-, LRR- and pyrin domain-containing protein 3 |
NOX4 | NADPH oxidase 4 |
OXPHOS | Oxidative phosphorylation |
PAMPs | Pathogen-associated molecular patterns |
PAX4 | Paired box gene 4 |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PKC | Protein kinase C |
PPARα | Peroxisome proliferator-activated receptor alpha |
PRRs | Pattern recognition receptors |
RIPK3 | Receptor-interacting serine/threonine-protein kinase 3 |
ROS | Reactive oxygen species |
SIRT1 | Sirtuin 1 |
SLD | Steatotic liver disease |
SREBP-1c | Sterol regulatory element-binding protein 1c |
STING | Stimulator of interferon genes |
T2DM | Type 2 diabetes mellitus |
TBK1 | TANK-binding kinase 1 |
TFAM | Mitochondrial transcription factor A |
TGF-β | Transforming growth factor beta |
TLR4 | Toll-like receptor 4 |
TLR9 | Toll-like receptor 9 |
TNF-α | Tumor necrosis factor alpha |
UCP1 | Uncoupling protein 1 |
USP29 | Ubiquitin-specific protease 29 |
VDAC | Voltage-dependent anion channel |
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Drug | Mechanism & Molecular Target | Developer | ClinicalTrials.gov Identifier | Phase | References |
---|---|---|---|---|---|
Anakinra | Recombinant IL-1 receptor antagonist; blocks IL-1α/β signaling | Swedish Orphan Biovitrum | NCT00303394 | 2 | [80] |
Canakinumab | Human monoclonal antibody against IL-1β; reduces systemic inflammation | Novartis | NCT01327846 (CANTOS trial) | 3 CVOT | [85] |
LY2189102 | Neutralizing IL-1β; inhibits IL-1β mediated inflammatory signaling | Eli Lilly | NCT00711556 | 2 | [86] |
Salsalate | Non-acetylated salicylate; inhibits IKKβ/NF-κB activation | Generic; studied in T2DM | NCT00799643 (TINSAL trials by NIH) | 2/3 | [87] |
Colchicine | Anti-inflammatory alkaloid; disrupts microtubules, inhibiting NLRP3 inflammasome activation | Generic; repurposed for T2DM inflammation (on going trials) | NCT04181996 (CADENCE trial) | 3 | [88,89] |
Dorzagliatin | First-in-class glucokinase allosteric activator; restores glucose sensing in β-cells & liver | Approved by China’s NMPA in 2022 as HuaTangNing® for T2DM. Completed Phase 3 trials in China. No approval in the U.S. | NCT03173391 & NCT03141073 (DAWN) | N/A | [90] |
MCC950 | Direct NLRP3 inflammasome inhibitor | Pfizer (CP-456773/CRID3); halted due to drug-induced hepatotoxicity | No T2DM clinical trial (Pre-clinical ONLY) | N/A | [84] |
Drug | Target | Developer | ClinicalTrials.gov Identifier | Phase | References |
---|---|---|---|---|---|
Lanifibranor | pan-PPAR (α/δ/γ) agonist | Inventiva | NCT04849728 | Phase 3 (ongoing) | [240] |
Efruxifermin (EFX) | FGF21 analogue (FGFR1c/2c/3c agonism) | Akero Therapeutics | NCT06215716 | Phase 3 (ongoing) | [241] |
Pegozafermin | FGF21 analogue | 89bio | NCT06318169 | Phase 3 (ongoing) | [242,243] |
Survodutide (BI-456906) | Dual GLP-1/Glucagon receptor agonist | Boehringer Ingelheim · Zealand Pharma | NCT06632444; NCT06632457 | Phase 3 (ongoing) | [244,245] |
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Choi, W.; Woo, G.H.; Kwon, T.-H.; Jeon, J.-H. Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction. Int. J. Mol. Sci. 2025, 26, 9715. https://doi.org/10.3390/ijms26199715
Choi W, Woo GH, Kwon T-H, Jeon J-H. Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction. International Journal of Molecular Sciences. 2025; 26(19):9715. https://doi.org/10.3390/ijms26199715
Chicago/Turabian StyleChoi, Wooyoung, Gun Ha Woo, Tae-Hwan Kwon, and Jae-Han Jeon. 2025. "Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction" International Journal of Molecular Sciences 26, no. 19: 9715. https://doi.org/10.3390/ijms26199715
APA StyleChoi, W., Woo, G. H., Kwon, T.-H., & Jeon, J.-H. (2025). Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction. International Journal of Molecular Sciences, 26(19), 9715. https://doi.org/10.3390/ijms26199715