Beyond glycemic control: How semaglutide reshapes intestinal neuroception via transforming growth factor-β/brain-derived neurotrophic factor signaling hubs

Table 2 In vitro and in vivo experimental evidence supporting the mechanisms of action of semaglutide

Evidence type	Experimental model	Intervention/treatment	Key findings and outcomes	Core targets/pathways involved	Ref.
In vitro	Human neuroblastoma SH-SY5Y cells	Treatment with GLP-1	Upregulated synaptic protein and neuronal receptor expression; blocked by PI3K inhibitor LY294002	PI3K/Akt signaling axis	[34]
	Hepatic stellate cell line LX-2	Exosomes derived from serum of T2DM patients treated with semaglutide	Reduced expression of fibrotic markers	TGF-β/Smad signaling pathway	[37]
In vivo	Streptozotocin-induced mouse model of sporadic Alzheimer’s disease	GLP-1 receptor agonist treatment	Increased hippocampal p-GSK-3β (Ser9), p-CREB (Ser133), and BDNF levels; decreased Aβ deposition and tau phosphorylation	GSK-3β/CREB/BDNF neuroprotective pathway	[33]
	High-fat diet-induced mouse model of diabetic cardiomyopathy	GLP-1RA	Inhibited cardiomyocyte lipid accumulation; downregulated TGF-β1, collagen I/III, and oxidative stress; attenuated myocardial fibrosis and improved cardiac function	TGF-β signaling; oxidative stress; fibrosis	[38]

GLP-1R: Glucagon-like peptide-1; PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B; T2DM: Type 2 diabetes mellitus; TGF-β: Transforming growth factor-β; p-GSK: Phosphorylated glycogen synthase kinase-3β; p-CREB: Phosphorylated cyclic adenosine monophosphate-response element-binding; Aβ: Amyloid-β; CREB: Cyclic adenosine monophosphate-response element-binding; BDNF: Brain-derived neurotrophic factor; GLP-1RA: Glucagon-like peptide-1 receptor agonist.