A Combination of Plant-Derived Extracts Modulates Nutrient-Responsive Metabolic Signalling in an In Vitro Gut–Liver–Adipose Model

Background/Objectives: Glucagon-like peptide-1 (GLP-1) is a nutritionally regulated incretin involved in the coordination of intestinal, hepatic, and adipose metabolic responses. Although plant-derived extracts are increasingly investigated for their metabolic effects, mechanistic evidence integrating multiple metabolic tissues remains limited. This study aimed to investigate the molecular effects of a combination of plant-derived extracts in an integrated in vitro gut–liver–adipose model. Methods: Differentiated Caco-2 monolayers were exposed to a standardised combination of plant-derived extracts obtained from Gastrodia elata, Morus alba, and Paeonia lactiflora. GLP-1 secretion and epithelial barrier integrity were assessed. Conditioned media from intestinal cells were applied to HepG2 hepatocytes, and downstream effects on lipid metabolism-related pathways were evaluated. Subsequently, conditioned media from hepatic cells were applied to differentiated 3T3-L1 adipocytes to assess lipid accumulation and metabolic signalling. Results: Exposure of intestinal cells to the extract combination significantly increased GLP-1 secretion without altering epithelial barrier integrity. Intestinal conditioned media were associated with reductions in intracellular triglyceride levels in hepatocytes and with modulation of markers linked to lipid handling, including resistin, FGF21, SREBP-1c, NRF2, Src, AMPK, SIRT1, and PGC1α, suggesting GLP-1-associated effects. In adipocytes, hepatic conditioned media decreased lipid accumulation and increased the levels of metabolic markers associated with adipocyte browning-related signalling, including UCP1, NOS, SIRT1, and STAT3. Conclusions: Within the limitations of this in vitro multi-organ model, these findings suggest that the tested combination of plant-derived extracts modulates cellular pathways related to GLP-1-associated metabolic signalling across intestinal, hepatic, and adipose systems. These results should be interpreted as mechanistic and hypothesis-generating, and further in vivo and clinical studies are required to confirm their physiological relevance.