Serum and Adipose Tissue Amino Acid Homeostasis in the Metabolically Healthy Obese

A subgroup
of obese individuals, referred to as metabolically healthy
obese (MHO), have preserved insulin sensitivity and a normal lipid
profile despite being obese. The molecular basis for this improved
cardiometabolic profile remains unclear. Our objective was to integrate
metabolite and gene expression profiling to elucidate the molecular
distinctions between MHO and metabolically unhealthy obese (MUO) phenotypes.
A subset of individuals were selected from the Diabetes Risk Assessment
study and classified into three groups using anthropometric and clinical
measurements: lean healthy (LH), MHO, and MUO. Serum metabolites were
profiled using gas chromatography coupled to mass spectrometry. Multivariate
data analysis uncovered metabolites that differed between groups,
and these were subsequently validated by capillary electrophoresis
coupled to mass spectrometry. Subcutaneous adipose tissue (SAT) gene
expression profiling using microarrays was performed in parallel.
Amino acids were the most relevant class of metabolites distinguishing
MHO from MUO individuals. Serum levels of glutamic acid, valine, and
isoleucine were positively associated (i.e., LH < MHO < MUO)
with homeostasis model assessment-insulin resistance (HOMA-IR) and
glycated hemoglobin (HbA1c) values, while leucine was only correlated
with HOMA-IR. The glutamine-to-glutamic acid ratio and glycine were
inversely correlated (i.e., LH > MHO > MUO) with HbA1c values.
Concomitantly,
SAT gene expression profiling revealed that genes related to branched-chain
amino acid catabolism and the tricarboxylic acid cycle were less down-regulated
in MHO individuals compared to MUO individuals. Together, this integrated
analysis revealed that MHO individuals have an intermediate amino
acid homeostasis compared to LH and MUO individuals.