Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered
amino acid profiles to be associated with
obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of
obesity and to explore potential strategies to mitigate
obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and
obesity. Based on the findings, we hypothesized that restriction of
branched-chain amino acids (BCAAs),
phenylalanine, or
tryptophan may prevent
obesity and tested our hypothesis in a
dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and
obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA,
phenylalanine,
tryptophan, and
phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum
glucose and
insulin at levels similar to those in the standard chow group, and prevented
obesity, adipocyte
hypertrophy, adipose
inflammation, and
insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA,
phenylalanine,
tryptophan, and
phospholipid metabolic pathways, are altered in
obesity and restriction of BCAAs within a HFD can prevent the development of
obesity and
insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced
obesity.