Targeting adipose remodeling: Synergistic mechanisms of drugs and adipose-derived stem cells in obese type 2 diabetes mellitus

Table 5 Key adipokines and inflammatory mediators associated with obesity and diabetes

Molecule	Category	Major source	Action on insulin signaling	Regulation trend (in obesity)	Regulation evidence by drugs/ADSCs
Leptin	Proinflammatory adipokine	VAT > SAT	Promotes IRS-1 Ser P, inhibits PI3K/Akt	↑	Downregulated by GLP-1RA; indirectly inhibited by ADSC EVs
Adiponectin	Anti-inflammatory/sensitizing	SAT	Activates AMPK/PPARα	↓	Upregulated by pioglitazone, SGLT-2 inhibitors
TNF-α	Classical proinflammatory cytokine	M1 macrophages, hypertrophic adipocytes	IKKβ/NF-κB AND JNK → promotes IRS-1 Ser P	↑	Downregulated by pioglitazone, metformin, ADSC EVs
IL-6	Proinflammatory cytokine	Same as above	SOCS3 inhibits IRS-1	↑	Suppressed via ADSC-derived IL-10 axis
IL-10	Anti-inflammatory cytokine	M2 macrophages, ADSCs	Inhibits NF-κB/JNK, enhances insulin signaling	↓	Healthy ADSC EVs → promote M2 macrophage polarization↑

ADSCs: Adipose-derived stem cells; VAT: Visceral adipose tissue; SAT: Subcutaneous adipose tissue; IRS-1: Insulin receptor substrate 1; Ser P: Serine phosphorylation; PI3K/Akt: Phosphoinositide 3-kinase/protein kinase B; GLP-1RA: Glucagon-like peptide-1 receptor agonist; EVs: Extracellular vesicles; AMPK: Adenosine monophosphate-activated protein kinase; PPARα: Peroxisome proliferator-activated receptor alpha; SGLT-2: Sodium-glucose cotransporter 2; TNF-α: Tumor necrosis factor alpha; M1: Classically activated macrophage (proinflammatory phenotype); IKKβ: IκB kinase beta; JNK: C-Jun N-terminal kinase; IL-6: Interleukin 6; IL-10: Interleukin 10; SOCS3: Suppressor of cytokine signaling 3; M2: Alternatively activated macrophage (anti-inflammatory phenotype); NF-κB: Nuclear factor kappa B.