👤 Christos S Mantzoros

Medications targeting the leptin and Apolipoprotein CIII (APOC3) pathways are currently under development for the treatment of hypertriglyceridaemia. Given that both pathways are implicated in triglyceride regulation, it is unknown whether they function independently or interact under physiological conditions and under acute or long-term energy deficiency. APOC3 levels and their association with circulating lipids and lipoproteins were evaluated in the context of two randomised controlled studies. In Study-1, 15 healthy individuals were examined under three distinct conditions, each lasting 72 h: isocaloric feeding, fasting with placebo administration and fasting with leptin administered at replacement doses. In Study-2, 20 females with hypoleptinemia due to relative energy deficiency in sport (REDs) for a minimum of 6 months were treated with either leptin or a placebo for 36 weeks. In Study-1, APOC3 levels remained stable across all arms and were unaffected by leptin administration. In the fed state, APOC3 levels presented positive correlations with various VLDL, IDL, LDL and HDL sizes, and free fatty acids (FFA), most of which were not replicated in fasting. During complete energy deprivation, APOC3 was correlated with HDL molecules, glutamine and FFA, whereas its levels were positively associated only with FFA under leptin treatment. In Study-2, APOC3 levels were lower in the leptin group, but this was not a leptin-dependent effect. A positive correlation between APOC3 levels and HDL was observed in the leptin group. These results contribute towards our better understanding of the intricate nature of lipid regulation under energy deficiency, suggesting that medications targeting the leptin and APOC3 pathways act through different metabolic pathways and thus may have independent effects from each other in regulating triglycerides. Show less

Severe early‑onset obesity is mainly attributed to single gene variations of the hypothalamic leptin‑melanocortin system, which is critical for controlling the balance between appetite and energy expenditure. Adenylate cyclase 3 (ADCY3), a transmembrane enzyme localized in primary neuronal cilia, is a key genetic candidate, which appears to have an essential role in regulating body weight. The present study aimed to identify ADCY3 genetic variants in severely obese young patients of Greek‑Cypriot origin by genomic sequencing. Apart from previously reported variants, the novel and probably pathogenic variant c.349T>A, causing a p.Leu117Met substitution within one of the two pseudo‑symmetric halves of the transmembrane part of the protein, was reported. Molecular modelling analysis used to delineate bonding interactions within the mutated protein structure strongly suggested a change in interactive forces and energy levels affecting the pseudo‑twofold symmetry of the transmembrane domain of the protein and probably its catalytic function. These results support the involvement of ADCY3 in the pathology of the disease and point towards the requirement of defining protein function and evaluating the clinical significance of the detected variants. Show less