Konstantinos Stefanakis

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

Aim: To investigate growth/differentiation factor 15 (GDF‐15) levels in response to antiobesity medications, namely, liraglutide (Lira) and naltrexone/bupropion (N/B), in individuals with overweight or obesity. Materials and Methods: This was a prospective, non‐randomized clinical trial with a two‐arm, parallel design. A total of 42 individuals with overweight or obesity without type 1 or type 2 diabetes mellitus were enrolled. The participants received either Lira 3 mg or N/B 32/360 mg, along with diet and exercise, according to comorbidities, cost and method of administration. Participants underwent clinical and laboratory measurements at baseline, as well as at the 3‐ and 6‐month time points. Anthropometric measurements and body composition analysis via bioelectrical impendence analysis were performed. Total blood samples for GDF‐15 and H‐specific GDF‐15 were collected in the fasting state and every 30 min for 3 h after the consumption of a standardized mixed meal. Results: Overall, participants' weight was reduced by 9.29 ± 5.34 kg at Month 3 and 11.52 ± 7.52 kg at Month 6. Total and H‐specific GDF‐15 levels did not show significant changes during the mixed meal compared to values before the meal when all participants were examined at baseline, and at 3 and 6 month follow‐ups. No statistical significance was found when participants were examined by subgroup (Lira vs. N/B). No significant differences between treatment groups in postprandial area under the curve (AUC) or incremental AUC values were found at baseline or in the follow‐up months with regard to total and H‐specific GDF‐15 levels. Conclusion: Neither total nor H‐specific GDF‐15 levels are affected by Lira or N/B treatment in patients with overweight or obesity.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.