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

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.