Indirect Calorimetry-Based Novel Approach for Evaluating Metabolic Flexibility and Its Association with Circulating Metabolic Markers in Middle-Aged Subjects.

We propose a novel method for assessing metabolic flexibility (MF) through indirect calorimetry. A total of twenty healthy volunteers (10 females; 10 males) aged 45-65 were categorized into a Low-Intensity activity group (LI, 0-1 session of 1 h per week) and a High-Intensity activity group (HI, 5-6 sessions of 2 h per week). Volunteers underwent a stepwise exercise test on a cycle ergometer, connected to a calorimeter, to examine respiratory gas exchange to evaluate peak fatty acid Oxidation (PFO) and peak carbohydrate oxidation (PCO). Circulating peroxisome proliferator-activated receptor α (PPARα) biomarkers, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio and N-oleoylethanolamine (OEA), and the endocannabinoid- 2-arachidonoylglycerol (2-AG), were evaluated. We developed two MF parameters: the MF index (MFI), calculated by the product of PFO normalized per kg of fat-free mass (FFM) and the percentage of VO2max at PFO, and the peak energy substrates' oxidation (PESO), computed by summing the kilocalories from the PFO and PCO, normalized per kg FFM. The MFI and PESO were significantly different between the HI and LI groups, showing strong correlations with the circulating bioactive substances. Higher DHA/EPA ratio (p ≤ 0.05) and OEA (p ≤ 0.01), but lower 2-AG levels (p ≤ 0.01) were found in the HI group. These new parameters successfully established a functional link between MF and the balance of PPARα/endocannabinoid systems.

Impact of prenatal THC exposure on lipid metabolism and microbiota composition in rat offspring.

Objective: Recent studies have demonstrated that prenatal exposure to the psychoactive ingredient of cannabis that is tetrahydrocannabinol (THC) disrupts fatty acid (FA) signaling pathways in the developing brain, potentially linking to psychopathologic consequences. Our research aims to investigate whether changes in midbrain FA metabolism are linked to modifications in peripheral metabolism of FAs and shifts in microbiota composition. Methods: In order to model prenatal exposure to THC (PTE) in rats, Sprague Dawley dams were systemically administered with THC (2 mg/kg, s.c.) or vehicle once daily from gestational day 5-20. To evaluate the metabolic impact of PTE in the offspring during preadolescence (postnatal day, PND, 25-28), we analyzed FA profiles and their bioactive metabolites in liver and midbrain tissues, and microbiota alterations. Results: Our findings indicate that PTE leads to sex-specific metabolic changes. In both sexes, PTE resulted in increased liver de novo lipogenesis (DNL) and alterations in FA profiles, as well as changes in N-acylethanolamines (NAEs), ligands of peroxisome proliferator-activated receptor alpha (PPAR-α). In females only, PTE influenced gene expression of PPAR-α and fibroblast growth factor 21 (Fgf21). In male offspring only, PTE was associated with significantly reduced fasting glycaemia and with alterations in the levels of midbrain NAEs. Our analysis of the progeny gut microbiota revealed sex-dependent effects of PTE, notably an increased abundance of Ileibacterium in PTE-exposed male offspring, a change previously associated with the long-term effects of a maternal unbalanced diet. Conclusions: Our data suggest that in male PTE offspring a reduced fasting glycaemia, resulting from increased liver DNL and the absence of a compensatory effect by Ppar-α and FGF21 on glycemic homeostasis, are associated to alterations in midbrain NAEs ligands of PPAR-α. These metabolic changes within the midbrain, along with Ileibacterium abundance, may partly elucidate the heightened susceptibility to psychopathologic conditions previously observed in male offspring following PTE.