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

Table 1 Metabolic and inflammatory characteristics of visceral adipose tissue vs subcutaneous adipose tissue

Dimension	VAT	SAT
Adipocyte size/insulin sensitivity	Large adipocytes, insulin-resistant	Small adipocytes, insulin-sensitive
Proinflammatory/anti-inflammatory profile	IL-6 (↑), TNF-α (↑), resistin (↑)	Adiponectin (↑)
Lipolysis/FFA output	High basal lipolysis, FFA enters portal circulation first	Lower lipolysis, buffers postprandial FFA
Hypoxia/ROS and mitochondrial function	Marked hypoxia, ROS (↑), mitochondrial dysfunction	Relatively preserved mitochondrial function
ECM remodeling and fibrosis	ECM deposition (↑), prone to fibrosis	Mild
Macrophage infiltration	Increased M1 macrophages, crown-like structures prominent	Lower inflammatory infiltration

VAT: Visceral adipose tissue; SAT: Subcutaneous adipose tissue; IL-6: Interleukin 6; TNF-α: Tumor necrosis factor alpha; FFA: Free fatty acid; ROS: Reactive oxygen species; ECM: Extracellular matrix; M1: Classically activated macrophage (proinflammatory phenotype).

Table 2 Summary of major drugs targeting fat distribution and their combined therapeutic strategies and mechanisms of action

Drug/regimen	Primary target	Key signaling pathway	Main affected fat depot	Body weight impact	Key metabolic benefits
Pioglitazone	PPARγ	PPARγ: Promotes adipocyte differentiation, increases adiponectin, anti-inflammatory	Subcutaneous fat (↑), visceral fat (↓)	Increased (mainly subcutaneous)	Improves insulin sensitivity, redistributes fat, alleviates lipotoxicity and inflammation
Metformin	AMPK	AMPK: Inhibits mTORC1, promotes FA oxidation, anti-inflammatory	Visceral and hepatic fat (↓)	Decreased or weight-neutral	Lowers glucose, anti-lipogenesis, promotes lipid oxidation, reduces inflammation, and improves adipokine profile
Pioglitazone + metformin	PPARγ + AMPK	Fat redistribution (PPARγ) + improved glucose metabolism (AMPK)	Subcutaneous fat (↑), visceral fat (↓)	Balanced	Complementary effects improve fat deposition and insulin resistance, broad metabolic improvement
GLP-1RA + metformin	GLP-1R + AMPK	Appetite suppression, insulin promotion (GLP-1R) + lipid oxidation (AMPK)	Visceral fat (↓) > subcutaneous fat (↓)	Decreased significantly	Antihyperglycemic + weight loss + visceral fat optimization, improved adipokines, anti-inflammatory
SGLT-2i + metformin	SGLT-2 + AMPK	Calorie loss via glycosuria (SGLT-2) + anti-lipogenesis, lipid oxidation (AMPK)	Abdominal, hepatic, and perirenal fat (↓)	Decreased (mainly fat reduction)	Glycemic control + fat loss + anti-inflammatory, reduces lipotoxicity, enhances insulin sensitivity
GLP-1RA + SGLT-2i	GLP-1R + SGLT-2	Dual mechanism: Appetite suppression + urinary glucose excretion	Visceral and hepatic fat (marked) (↓)	Decreased (more pronounced)	Multitarget fat reduction, weight loss, metabolic enhancement, cardiovascular and renal benefits
Pioglitazone + GLP-1RA or SGLT-2i	PPARγ + GLP-1R/SGLT-2	Fat redistribution reprogramming (PPARγ) + fat reduction/glycemic control (GLP-1RA/SGLT-2i)	Fat in multiple depots (↓), subcutaneous storage (↑)	Decreased (via GLP-1RA or SGLT-2i)	Multi-action: Glucose lowering, anti-inflammatory, improved adipokines/Lipotoxicity, better cardiovascular outcomes

PPARγ: Peroxisome proliferator-activated receptor gamma; AMPK: AMP-activated protein kinase; mTORC1: Mammalian target of rapamycin complex 1; FA: Fatty acid; GLP-1RA: Glucagon-like peptide-1 receptor agonist; GLP-1R: Glucagon-like peptide-1 receptor; SGLT-2: Sodium-glucose cotransporter 2; SGLT-2i: Sodium-glucose cotransporter 2 inhibitor.

Table 3 Phenotypic differences and differentiation potential of adipose-derived stem cells from various sources

Source	Typical surface markers	Differentiation potential/characteristics
Subcutaneous fat	CD73+, CD90+, CD105+; CD34-/Low, CD45-	Strong adipogenic differentiation; moderate osteogenic/chondrogenic potential; suitable for tissue engineering
Visceral (intra-abdominal) fat	Same as subcutaneous; some studies report SC-ASCs (high CD10) vs VS-ASCs (high CD200)	Slight variation in adipogenic potential; possibly different impacts on metabolic regulation
Brown adipose tissue	Same as MSC markers; commonly express Sca-1, CD29, CD49 in experimental settings	Stronger differentiation capacity; high proliferation; excellent adipogenic, osteogenic, and myogenic potential
Others (e.g., retroperitoneal, periovarian fat)	Similar MSC markers; may include more vascular-related markers (e.g., CD146)	Broad differentiation spectrum; capable of differentiating into mitochondria-rich cell lineages; less studied

CD73: Cluster of differentiation 73; CD90: Cluster of differentiation 90; CD105: Cluster of differentiation 105; CD34: Cluster of differentiation 34; CD45: Cluster of differentiation 45; SC-ASCs: Subcutaneous adipose-derived stem cells; CD10: Cluster of differentiation 10; VS-ASCs: Visceral adipose-derived stem cells; MSC: Mesenchymal stem cell; Sca-1: Stem cell antigen-1; CD29: Cluster of differentiation 29; CD49: Cluster of differentiation 49; CD146: Cluster of differentiation 146.

Table 4 Secretory factors of adipose-derived stem cells and their metabolic and immunomodulatory effects in target tissues

Category of secretion	Representative molecules/miRNAs	Main target tissues or cells	Typical receptors/signaling pathways	Expected metabolic and inflammatory effects
Cytokines	IL-10, TGF-β, VEGF, HGF	VAT, SAT, liver, skeletal muscle, macrophages	JAK1/Tyk2-STAT3; SMAD2/3; VEGFR2-PI3K/Akt	Inhibit NF-κB and JNK-mediated inflammation; promote angiogenesis and tissue repair; enhance insulin signaling throughput
Exosomal miRNAs	miR-223-3p, miR-29a, miR-155, miR-210	Hepatocytes, adipocytes, macrophages	Target E2F1, SOCS1/STAT1, SHIP1, IRAK1/NF-κB	Alleviate hepatic steatosis and fibrosis; modulate macrophage polarization; promote adipose browning and adiponectin secretion
Growth/chemotactic factors	Ang-1, FGF, IGF-1, MCP-1	Vascular endothelium, fibroblasts, immune cells	Tie2-Akt; FGFR-MAPK; CCR2	Promote vascular remodeling; chemotactic regulation of immune cells; improve tissue microcirculation
Antioxidant regulatory axis	PGC-1α-induced upregulation of SOD2, UCP1	White/brown adipocytes	PGC-1α-TFAM; UCP1-uncoupling	Enhance mitochondrial biogenesis and oxidative phosphorylation; reduce ROS load; increase energy expenditure

miRNA: MicroRNA; IL-10: Interleukin 10; TGF-β: Transforming growth factor beta; VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; VAT: Visceral adipose tissue; SAT: Subcutaneous adipose tissue; JAK1: Janus kinase 1; Tyk2: Tyrosine kinase 2; STAT3: Signal transducer and activator of transcription 3; SMAD2/3: Mothers against decapentaplegic homolog 2/3; VEGFR2: Vascular endothelial growth factor receptor 2; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; NF-κB: Nuclear factor kappa B; JNK: C-Jun N-terminal kinase; E2F1: E2F transcription factor 1; SOCS1: Suppressor of cytokine signaling 1; SHIP1: SH2-containing inositol phosphatase 1; IRAK1: Interleukin-1 receptor-associated kinase 1; Ang-1: Angiopoietin 1; FGF: Fibroblast growth factor; IGF-1: Insulin-like growth factor 1; MCP-1: Monocyte chemoattractant protein 1; Tie2: Tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 2; FGFR: Fibroblast growth factor receptor; MAPK: Mitogen-activated protein kinase; CCR2: C-C chemokine receptor type 2; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SOD2: Superoxide dismutase 2; UCP1: Uncoupling protein 1; TFAM: Transcription factor A, mitochondrial; ROS: Reactive oxygen species; miR: MicroRNA.

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.

Table 6 Targeted pathways and metabolic effects of adipose-derived stem cell-derived exosomal microRNAs

miRNA	Major direct target genes/pathways	Target tissues/cells	Metabolic or inflammatory effects	Evidence type1
miR-223-3p	E2F1 → Inhibits adipogenesis/fibrosis	Hepatocytes	Reduces hepatic lipid accumulation and fibrosis	HFD mice (in vivo)/HepG2 (in vitro)
miR-29a	SOCS1/STAT1	Macrophages	Inhibits M1 polarization, decreases TNF-α/IL-6	LPS-stimulated RAW264.7/mice
miR-155	SHIP1/SOCS1	Macrophages	Promotes M1 polarization, amplifies inflammation	Functional antagonism in vitro
miR-34a	SIRT1/FGF21	Liver and adipose tissue	Inhibits browning, promotes adipogenesis	DIO mice (in vivo)
miR-210	IRAK1/NF-κB	Liver, skeletal muscle	Reduces inflammation, improves insulin sensitivity	db/db mice (in vivo)
miR-126	IRS-1/PI3K-Akt	Endothelial cells	Promotes angiogenesis, improves insulin signaling	STZ rats (in vivo)/HUVEC

¹Evidence types include in vivo animal models and in vitro cell line experiments. miRNA: MicroRNA; E2F1: E2F transcription factor 1; SOCS1: Suppressor of cytokine signaling 1; STAT1: Signal transducer and activator of transcription 1; SHIP1: SH2-containing inositol phosphatase 1; SIRT1: Sirtuin 1; FGF21: Fibroblast growth factor 21; IRAK1: Interleukin-1 receptor-associated kinase 1; NF-κB: Nuclear factor kappa B; IRS-1: Insulin receptor substrate 1; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin 6; HFD: High-fat diet; HepG2: Human hepatocellular carcinoma cell line; LPS: Lipopolysaccharide; RAW264.7: Murine macrophage cell line; DIO: Diet-induced obesity; db/db: Diabetic obese (leptin receptor-deficient) mouse model; STZ: Streptozotocin; HUVEC: Human umbilical vein endothelial cells; M1: Classically activated macrophage (proinflammatory phenotype); miR: MicroRNA.

Table 7 Mapping of combined therapy components to targeted complication pathways and endpoints

Combination	Dominant mechanism (within unified axis)	Target complication	Key endpoints	Notes
GLP-1RA + ADSC/EV	Reducing adipose inflammation → improved endothelial function; proangiogenic repair	ASCVD	MACE, FMD, hs-CRP	Weight loss enables ADSC efficacy
SGLT-2i + ADSC/EV	Hemodynamic unloading; anti-fibrosis + tubular regeneration	HF/CKD	HF hospitalization, eGFR slope, UACR	Monitor volume status
Metformin + ADSC/EV	AMPK activation; mitochondrial support + neurotrophic cues	Neuropathy	NCS, QST, CCM metrics	Consider B12 monitoring
Low-dose PPARγ + ADSC/EV	Adipose remodeling; anti-inflammation + anti-fibrosis	Multiorgan	Composite renal/cardiac endpoints	Consider edema risk

GLP-1RA: Glucagon-like peptide-1 receptor agonist; ADSC: Adipose-derived stem cell; EV: Extracellular vesicle; SGLT-2i: Sodium-glucose cotransporter-2 inhibitor; PPARγ: Peroxisome proliferator-activated receptor gamma; AMPK: Adenosine monophosphate-activated protein kinase; ASCVD: Atherosclerotic cardiovascular disease; HF: Heart failure; CKD: Chronic kidney disease; MACE: Major adverse cardiovascular events; FMD: Flow-mediated dilation; hs-CRP: High-sensitivity C-reactive protein; eGFR: Estimated glomerular filtration rate; UACR: Urinary albumin-to-creatinine ratio; NCS: Nerve conduction study; QST: Quantitative sensory testing; CCM: Corneal confocal microscopy; B12: Vitamin B12.