Nutrient-Derived Modulation of the Gremlin-1/BMP-4 Axis by White Tea Preserves Insulin Sensitivity During Early Diet-Induced Metabolic Dysregulation

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Abstract
Given the increasing burden of diet-induced metabolic dysregulation, preventive nutritional strategies targeting early insulin resistance are of growing interest. The aim of this study was to evaluate the effects of white tea supplementation on body weight gain, insulin resistance, and the Gremlin-1/Bone Morphogenetic Protein-4 (BMP-4) axis in visceral adipose tissue under high-fat diet conditions in a non-obese experimental model. Thirty-two male Sprague–Dawley rats were randomized into four groups (n = 8/group): standard diet (control), only high-fat diet (HFD), high-fat diet plus orlistat (ORL: 30 mg/kg/day), and high-fat diet plus white tea (WT: 5 mg/kg/day). Interventions were administered once daily by oral gavage for 12 weeks. Body weight was recorded weekly. At the end of the study, serum insulin, Gremlin-1, and BMP-4 and retroperitoneal adipose tissue Gremlin-1 and BMP-4 levels were measured by ELISA. Adipose tissue GREM1 gene expression was quantified by qRT-PCR. Insulin resistance was estimated using the HOMA-IR index. Appropriate statistical analyses were conducted in line with the study design and data distribution. High-fat feeding resulted in the highest HOMA-IR values, whereas white tea supplementation reduced HOMA-IR compared to the HFD group (p = 0.008). Body weight gain was increased in both the HFD and ORL groups compared to the control (p = 0.009 and p = 0.012, respectively). The lowest weight gain was observed in the WT group, which was lower than the HFD group (p = 0.044). GREM1 expression showed a 1.92-fold increase in the HFD group relative to the control, with smaller increases in the WT and ORL groups; however, intergroup differences did not reach statistical significance (p = 0.063). Serum BMP-4 levels were lower in the WT group compared to the control (p = 0.012), while tissue BMP-4 and Gremlin-1 levels did not differ between groups. Correlation analyses revealed a moderate inverse association between serum Gremlin-1 and serum BMP-4 (rho = −0.493, p = 0.011) and a moderate positive correlation between serum BMP-4 and HOMA-IR (rho = 0.564, p = 0.003). White tea supplementation attenuated body weight gain and preserved insulin sensitivity in a non-obese high-fat diet model, as evidenced by reduced weight gain and lower HOMA-IR values compared with high-fat feeding alone. These metabolic improvements were accompanied by coordinated changes in circulating components of the Gremlin-1/BMP-4 axis, including reduced serum BMP-4 levels and associations between BMP-4, Gremlin-1, and insulin resistance. Although tissue-level alterations were modest, the observed systemic patterns are consistent with an exploratory association between white tea intake and early metabolic signaling changes; however, definitive pathway modulation cannot be inferred from the present dataset. Collectively, these findings support white tea as a nutrient-derived bioactive with preventive metabolic potential during the early stages of diet-induced metabolic dysregulation, prior to the development of overt obesity.
Funding Information
  • Recep Tayyip Erdoğan University (TSA-2020-1166)

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