N. Zhang, N. Liu, G. Zhao, J. Yan, P. Zhang, X. Li, et al. (2025). Effects of a two-week modified ketogenic diet on circulating lipoprotein subclasses, GDF15, and FGF21 in obese adults. Journal of translational medicine, 23(1), 1244. https://doi.org/10.1186/s12967-025-07251-2

PubMed 41204286

[Abstract]
BACKGROUND: As key metabolic regulators, the roles of GDF15 and FGF21 in mediating the effects of modified ketogenic diet (MKD) on weight loss and lipoprotein remodeling in obese patients require further investigation.

PATIENTS AND METHODS: This study enrolled 30 metabolically healthy obese participants (BMI ≥ 28 kg/m²) for a 2-week MKD intervention. Using a self-controlled pre-post design, we performed measurements including body composition analysis, fasting serum GDF15 and FGF21 levels measurement, and serum lipoprotein subclass quantification at both baseline and post-intervention time points.

RESULTS: Following a 2-week MKD intervention, participants exhibited statistically significant reductions in body weight (96.14 ± 27.23 kg vs. 91.63 ± 26.47 kg; Δ4.8%, P < 0.001) and BMI (33.99 ± 6.08 kg/m2 vs. 32.41 ± 5.95 kg/m2; Δ4.7%, P < 0.001). Body fat parameters significantly improved, with body fat mass (BFM) and visceral fat area (VFA) decreasing by > 5%. Meanwhile, lean mass indices (SMM, SLM, FFM) remained stable (change < 3%). Serum biomarker analysis revealed that GDF15 levels increased significantly by 5.76% (P = 0.0377), whereas FGF21 levels decreased markedly by 51.91% (P = 0.0001). The apolipoprotein B/A1 ratio (t = 5.381, P < 0.001) and the LDL-c/HDL-c ratio (t = 5.095, P < 0.001) increased significantly. Furthermore, larger HDL-c subfractions (H1FC/H2FC) showed an upward trend, while smaller HDL-c subfractions (H3FC/H4FC) exhibited a downward trend. Among these changes, H2FC levels demonstrated the most pronounced elevation (t = 6.119, P < 0.001).

CONCLUSION: The short-term MKD intervention significantly improved adiposity metrics while elevating GDF15 and reducing FGF21 levels. These rapid metabolic adaptations induced potentially beneficial remodeling of HDL-c subclasses, highlighting novel effects beyond conventional lipid ratios.

TRIAL REGISTRATION: ChiCTR, ChiCTR2300071823. Registered 25 May 2023 - Prospective Registered, https://www.chictr.org.cn/bin/project/edit?pid=198176 .