The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.

OBJECTIVE: The present study aimed to compare measured and estimated resting metabolic rate (RMR) predicted by selected equations in patients with nonactive inflammatory bowel disease (IBD) on an outpatient university clinic regimen.
METHODS: Seventy-two adult (≥20 years) IBD patients (45 with Crohn\'s disease-CD) had RMR measured (mRMR) by indirect calorimetry and also estimated by predictive equations (Cunningham, Henry, Anjos et al., and Marra et al.). Body composition was assessed by DXA. Absolute Bias (estimated - mRMR) and % Bias (Bias/mRMR) were calculated. Agreement was assessed as the limit of agreement (LoA) in the Bland & Altman approach.
RESULTS: There was no difference in age, body composition and mRMR between individuals with CD (5414.2 ± 1023.7 kJ/day) and ulcerative colitis (5443.9 ± 1008.9 kJ/day). Among the equations, only the Anjos et al.\'s population-specific equation (-52.1 [642.0] kJ/day, P = 0.493; LoA: -1311; 1206 kJ/d) accurately estimated RMR. The equations of Marra et al. produced the highest % Bias (24.1 ± 14.8%). The Bland & Altman plots showed that the range of the LoA was relatively similar for all equations. In the simple regression analysis, the model with FFM resulted in a higher coefficient of determination (R2 = 0.51 for DC 0.74 for UC) compared to the model that included BM (R2 = 0.35 for DC and 0.65 for UC).
CONCLUSIONS: Among the equations analyzed, only Anjos et al.\'s accurately estimated RMR in outpatients with nonactive IBD. However, caution is advised when applying it at the individual level, due to the wide observed LoA.

UNASSIGNED: This cross-sectional study aimed to investigate the role of low energy availability (LEA) in the interplay between depression and disordered eating/eating disorders (DE/EDs) among female athletes. The International Olympic Committee consensus statement on Relative Energy Deficiency in Sport (REDs) identified depression as both an outcome of LEA and a secondary risk factor for REDs. However, the direct link between LEA and depression has yet to be fully established.
UNASSIGNED: We assessed 57 female athletes participating in weight-sensitive sports at different levels of competition training at least four times a week. Assessment was conducted using laboratory analyses, clinical interviews and the Patient Health Questionnaire-9 questionnaire. Participants were recruited through various channels, including German sports clubs, Olympic training centres, social media platforms and the distribution of flyers at competitions. Indicators of LEA were defined if at least two of the following three physiological indicators were present: menstrual disturbances, suppressed resting metabolic rate and suppressed thyroid hormones. Logistic and linear regression analysis were used to examine the relationship between LEA, depression and DE/ED.
UNASSIGNED: The lifetime prevalence of depressive disorders was 29.6%. 19% of the participants were diagnosed with an ED, and an additional 22.6% exhibited DE.LEA was not significantly associated with either lifetime prevalence of depressive disorders or current depressive symptoms. However, a significant association was found between depression and DE/ED in terms of both lifetime prevalence and current depressive symptoms. DE/ED increased the probability of lifetime prevalence of depressive disorders by 34% (19%-49%) compared with normal eating behaviour.
UNASSIGNED: We found no evidence that LEA is an independent factor for depression in female athletes. Its association with LEA and REDs appears to occur primarily in the presence of DE/ED.

BACKGROUND: Acute kidney injury patients on continuous renal replacement therapy are subjected to alterations in metabolism, which in turn are associated with worse clinical outcome and mortality. The aim of this study is to determine which metabolism indicators can be used as independent predictors of 30 days intensive care unit (ICU) mortality.
METHODS: This was a prospective observational study on critical care patients on renal replacement therapy. Integrated approach of metabolism evaluation was used, combining the energy expenditure measured by indirect calorimetry, bioelectrical impedance provided fat free mass index (FFMI), amino acid and glucose concentrations. ICU mortality was defined as all cause 30 days mortality. Regression analysis was conducted to determine the conventional and metabolism associated predictors of mortality.
RESULTS: The study was conducted between the 2021 March and 2022 October. 60 high mortality risk patients (APACHE II of 22.98 ± 7.87, 97% on vasopressors, 100% on mechanical ventilation) were included during the period of the study. The rate of 30 days ICU mortality was 50% (n = 30). Differences across survivors and non-survivors in metabolic predictors were noted in energy expenditure (kcal/kg/day) (19.79 ± 5.55 vs 10.04 ± 3.97 p = 0.013), amino acid concentrations (mmol/L) (2.40 ± 1.06 vs 1.87 ± 0.90 p = 0.040) and glucose concentrations (mmol/L) (7.89 ± 1.90 vs 10.04 ± 3.97 p = 0.010). No differences were noted in FFMI (23.38 ± 4.25 vs 21.95 ± 3.08 p = 0.158). In the final linear regression analysis model, lower energy expenditure (exp(B) = 0.852 CI95%: 0.741-0.979 p = 0.024) and higher glucose (exp(B) = 1.360 CI95%: 1.013-1.824 p = 0.041) remained as independent predictors of the higher mortality.
CONCLUSIONS: The results of the study imply strong association between the metabolic alterations and ICU outcome. Our findings suggest that lower systemic amino acid concentration, lower energy expenditure and higher systemic glucose concentration are predictive of 30 days ICU mortality.

Background/Objectives: A high level of specific metabolic capacity is essential for maximal sprinting in both male and female athletes. Various factors dictate sex differences in maximal power production and energy utilization. This study aims to compare the contribution of energy systems between male and female athletes with similar sport-specific physiological adaptations during a 15-s sprint exercise. Methods: The endurance group consisted of 17 males (23 ± 7 y) and 17 females (20 ± 2 y). The speed-power group included 14 males (21.1 ± 2.6 y) and 14 females (20 ± 3 y). The contribution of phosphagen, glycolytic, and aerobic systems was determined using the three-component PCr-LA-O2 method. Results: Significant differences were observed in the energy expenditure for all systems and total energy expenditure between males and females in both groups (p = 0.001-0.013). The energy expenditure in kJ for individual systems (phosphagen-glycolytic-aerobic) was 35:25:7 vs. 20:16:5 in endurance males vs. female athletes, respectively. In the speed-power group, male athletes expended 33:37:6 kJ and female athletes expended 21:25:4 kJ, respectively. The percentage proportions did not differ between males and females in any system. The contribution of the phosphagen-glycolytic-aerobic systems was 52:37:11 vs. 48:39:13 in endurance male and female athletes, respectively. For speed-power males vs. female athletes, the proportions were 42:50:8 vs. 41:50:9, respectively. Conclusions: Despite the differences in body composition, mechanical output, and absolute energy expenditure, the energy system contribution appears to have a similar metabolic effect between male and female athletes engaged in sprint exercises with similar sport-related adaptations. The magnitude and profile of sex differences are related to sports discipline.

Intravenous alpha-2-adrenergic receptor agonists reduce energy expenditure and lower the temperature when shivering begins in humans, allowing a decrease in core body temperature. Because there are few data about similar effects from oral drugs, we tested whether single oral doses of the sedative dexmedetomidine (1 µg/kg sublingual or 4 µg/kg swallowed) or the muscle relaxant tizanidine (8 mg or 16 mg), combined with surface cooling, reduce energy expenditure and core body temperature in humans. A total of 26 healthy participants completed 41 one-day laboratory studies measuring core body temperature using an ingested telemetry capsule and measuring energy expenditure using indirect calorimetry for up to 6 hours after drug ingestion. Dexmedetomidine induced a median 13% - 19% peak reduction and tizanidine induced a median 15% - 22% peak reduction in energy expenditure relative to baseline. Core body temperature decreased a median of 0.5°C - 0.6°C and 0.5°C - 0.7°C respectively. Decreases in temperature occurred after peak reductions in energy expenditure. Energy expenditure increased with a decrease in core temperature in control participants but did not occur after 4 µg/kg dexmedetomidine or 16 mg tizanidine. Plasma levels of dexmedetomidine but not tizanidine were related to mean temperature change. Decreases in heart rate, blood pressure, respiratory rate, cardiac stroke volume index, and cardiac index were associated with the change in metabolic rate after higher drug doses. We conclude that both oral dexmedetomidine and oral tizanidine reduce energy expenditure and allow decrease in core temperature in humans.

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction.

Crosstalk between peripheral metabolic organs and the central nervous system is essential for body weight control. At the base of the hypothalamus, β-tanycytes surround the portal capillaries and function as gatekeepers to facilitate transfer of substances from the circulation into the cerebrospinal fluid and vice versa. Here, we investigated the role of the neuroplasticity gene doublecortin-like (DCL), highly expressed by β-tanycytes, in body weight control and whole-body energy metabolism. We demonstrated that DCL-knockdown through a doxycycline-inducible shRNA expression system prevents body weight gain by reducing adiposity in mice. DCL-knockdown slightly increased whole-body energy expenditure possibly as a result of elevated circulating thyroid hormones. In white adipose tissue (WAT) triglyceride uptake was increased while the average adipocyte cell size was reduced. At histological level we observed clear signs of browning, and thus increased thermogenesis in WAT. We found no indications for stimulated thermogenesis in brown adipose tissue (BAT). Altogether, we demonstrate an important, though subtle, role of tanycytic DCL in body weight control through regulation of energy expenditure, and specifically WAT browning. Elucidating mechanisms underlying the role of DCL in regulating brain-peripheral crosstalk further might identify new treatment targets for obesity.

Several animal species use tools for foraging; however, very few manufacture and/or modify those tools. Humpback whales, which manufacture bubble-net tools while foraging, are among these rare species. Using animal-borne tag and unoccupied aerial system technologies, we examine bubble-nets manufactured by solitary humpback whales (Megaptera novaeangliae) in Southeast Alaska while feeding on krill. We demonstrate that the nets consist of internally tangential rings and suggest that whales actively control the number of rings in a net, net size and depth and the horizontal spacing between neighbouring bubbles. We argue that whales regulate these net structural elements to increase per-lunge prey intake by, on average, sevenfold. We measured breath rate and swimming and lunge kinematics to show that the resulting increase in prey density does not increase energetic expenditure. Our results provide a novel insight into how bubble-net tools manufactured by solitary foraging humpback whales act to increase foraging efficiency.

The mechanical efficiency of human locomotion has been studied extensively. The mechanical efficiency of the whole body occasionally exceeds muscle efficiency during bouncing type gaits. It is thought to occur due to elasticity and stiffness of the tendinomuscular system and neuromuscular functions, especially stretch reflexes. In addition, the lower limb joint kinetics affect mechanical efficiency. We investigated the impact of varying external work on mechanical efficiency and lower limb kinetics during repeated sledge jumping. Fifteen male runners performed sledge jumping for 4 minutes at 3 different sledge inclinations. Lower limb kinematics, ground reaction forces, and expired gases were analyzed. Mechanical efficiency did not differ according to sledge inclination. Mechanical efficiency correlated positively with the positive mechanical work of the knee and hip joints and the negative contribution of the hip joints. Conversely, it correlated negatively with both the positive and negative contributions of the ankle joint. This may be attributable to the greater workload in this study versus previous studies. To achieve greater external work, producing more mechanical energy at the proximal joint and transferring it to the distal joint could be an effective strategy for improving mechanical efficiency because of the greater force-generating capability of distal joint muscles.