Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children

Abstract

BackgroundLeptin and adiponectin communicate with organ systems in order to regulate energetic and metabolic homeostasis. Their different points of action have been well characterized; however, no study has investigated their interrelationship with the metabolism at the molecular level in vivo.ObjectiveTo examine the associations of leptin and adiponectin with the metabolic profile reflecting the intercellular and interorgan communication as well as activated metabolic pathways.Patients/MethodsWe measured plasma concentrations of leptin, adiponectin, and insulin along with concentrations of 196 metabolites in 400 healthy, fasting 8-years old German children who participated in the German Ulm Birth Cohort Study (UBCS). Using multiple linear mixed models, we evaluated the associations between hormones and metabolites.ResultsLeptin levels increased exponentially with increasing BMI. Leptin was furthermore strongly associated with alanine and aspartate (Bonferroni corrected P[PBF] = 5.7×10−8 and 1.7×10−6, respectively), and negatively associated to the sum of the non-esterified fatty acids (NEFA) and the sum of the long-chain acylcarnitines C12–C18 (PBF = 0.009 and 0.0001, respectively). Insulin showed a similar association pattern, although the associations were less strong than for leptin. Adiponectin was neither related to BMI nor to any metabolite.ConclusionAlthough children were presumably metabolically similar, we found strong associations of insulin and leptin with the metabolite profile. High alanine concentrations and the lower concentrations of NEFA in children with high fasting leptin concentrations might arise from an increased gluconeogenesis and from the disinhibiting effect of leptin on the carnitine-palmitoyltransferase-1, respectively. As insulin had the same trend towards these associations, both hormones seem to be related to processes that provide the body with energy in fasting state.

Leptin Concentration, Obesity, and Plasma Non-esterified Fatty Acid Levels in Children

“…Thus, the negative association between leptin levels and NEFA concentration found in prepubertal children in our study is surprising. In this sense, similar to our findings, the Ulm Birth Cohort Study, analyzing 8-year-old children, also showed that leptin was negatively associated to NEFA concentrations ( 13 ). The authors suggest that, at this age, leptin seems to be related to energy providing processes in the fasting state and highlight the involvement of leptin in the regulation of fatty acid oxidation.…”

“…It has been suggested that leptin has an important influence on NEFA metabolism ( 11 , 13 ) and that changes in adipokines secretion may precede changes in plasma NEFA concentrations ( 8 ).…”

“…The authors suggest that, at this age, leptin seems to be related to energy providing processes in the fasting state and highlight the involvement of leptin in the regulation of fatty acid oxidation. They suggest that the inverse relationship between leptin and NEFA concentrations could be explained by the fact that NEFA are taken up by tissue for oxidation induced by higher CPT-1 activity stimulated by leptin ( 13 ).…”

An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children

“…The amino acids alanine and tyrosine were positively related to HOMA in our analysis. Alanine was previously found to be positively associated with fasting insulin and leptin levels, pointing towards its role in gluconeogenesis and insulin resistance onset 56 . Tyrosine has previously been related to lower BMI z-score but also to insulin resistance in obese children 33 .…”

Replication and mediation of the association between the metabolome and clinical markers of metabolic health in an adolescent cohort study

“…Most studies included in the SLR were in exclusively adult study populations. Three studies studied children 53 , 61 , 62 and two studies 52 , 57 adolescents and young adults. Age is another influential factor in the composition of the metabolome that may need additional adjustment strategies in the long term 63 .…”