Optimized Nutri-Dense meals versus a low-carbohydrate high-fat diet: an exploratory randomized controlled trial
Abstract
Micronutrient adequacy, beyond macronutrient balance, may matter for health, yet the effects of low-carbohydrate, high-fat (LCHF) diets on obesity remain unclear. This exploratory three-arm, single-blind randomized controlled trial (N = 300) compared, over 4 weeks, meals optimized to the Japanese Dietary Reference Intakes (DRI; Opti meals, matched macronutrient ratio and 26 micronutrients), a micronutrient-insufficient control diet, and LCHF Opti meals (lower carbohydrate–fat ratio, identical micronutrients). In this partial report, primary outcomes were visceral fat area and salivary cortisol/melatonin, the device-derived streams of that set being reported separately; prespecified secondary outcomes were LDL-cholesterol, systolic/diastolic blood pressure (SBP/DBP), gut microbiota, serum metabolome, and DNA-methylation (DNAm) epigenetic age, analyzed in an exploratory, hypothesis-generating manner. Neither primary outcome differed between groups. LDL-cholesterol decreased in both Opti and LCHF Opti groups versus control, and SBP in the LCHF Opti group. Exploratory analyses showed shifts in gut microbiota and metabolites. In a small subgroup of older male participants (n = 10 per group), the Opti group showed lower PhenoAge, a DNA-methylation measure of biological age linked to mortality risk. Post-hoc machine learning predicted cardiometabolic responders (ROC-AUC 0.71–0.76). DRI-based meals did not outperform the comparators on the primary endpoints; the secondary findings are hypothesis-generating and require confirmation. Clinical Trial Registry number: UMIN000050103, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000056407 (approval: 23/1/2023).
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BibTeX
@article{hishikawa2026optimized,
title = {{Optimized Nutri-Dense meals versus a low-carbohydrate high-fat diet: an exploratory randomized controlled trial}},
author = {Akihito Hishikawa and Shintaro Fujii and Jun Iimura and Naohisa Shobako and Takuo Nakazeko and Yukio Hirano and Futoshi Nakamura and Masahiro Yagihashi and Atsushi Nakajima and Yoshinori Katsumata and Kenichiro Kinouchi and Jun Yoshino and Junichiro Irie and Kaori Hayashi and Hiroshi Itoh},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73421-x},
url = {https://www.nature.com/articles/s41598-026-73421-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Optimized Nutri-Dense meals versus a low-carbohydrate high-fat diet: an exploratory randomized controlled trial
AU - Akihito Hishikawa
AU - Shintaro Fujii
AU - Jun Iimura
AU - Naohisa Shobako
AU - Takuo Nakazeko
AU - Yukio Hirano
AU - Futoshi Nakamura
AU - Masahiro Yagihashi
AU - Atsushi Nakajima
AU - Yoshinori Katsumata
AU - Kenichiro Kinouchi
AU - Jun Yoshino
AU - Junichiro Irie
AU - Kaori Hayashi
AU - Hiroshi Itoh
PY - 2026
DA - 2026/10/03
JO - Scientific Reports
DO - 10.1038/s41598-026-73421-x
UR - https://www.nature.com/articles/s41598-026-73421-x
AB - Micronutrient adequacy, beyond macronutrient balance, may matter for health, yet the effects of low-carbohydrate, high-fat (LCHF) diets on obesity remain unclear. This exploratory three-arm, single-blind randomized controlled trial (N = 300) compared, over 4 weeks, meals optimized to the Japanese Dietary Reference Intakes (DRI; Opti meals, matched macronutrient ratio and 26 micronutrients), a micronutrient-insufficient control diet, and LCHF Opti meals (lower carbohydrate–fat ratio, identical micronutrients). In this partial report, primary outcomes were visceral fat area and salivary cortisol/melatonin, the device-derived streams of that set being reported separately; prespecified secondary outcomes were LDL-cholesterol, systolic/diastolic blood pressure (SBP/DBP), gut microbiota, serum metabolome, and DNA-methylation (DNAm) epigenetic age, analyzed in an exploratory, hypothesis-generating manner. Neither primary outcome differed between groups. LDL-cholesterol decreased in both Opti and LCHF Opti groups versus control, and SBP in the LCHF Opti group. Exploratory analyses showed shifts in gut microbiota and metabolites. In a small subgroup of older male participants (n = 10 per group), the Opti group showed lower PhenoAge, a DNA-methylation measure of biological age linked to mortality risk. Post-hoc machine learning predicted cardiometabolic responders (ROC-AUC 0.71–0.76). DRI-based meals did not outperform the comparators on the primary endpoints; the secondary findings are hypothesis-generating and require confirmation. Clinical Trial Registry number: UMIN000050103, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000056407 (approval: 23/1/2023).
SN - 2045-2322
ER -