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Characteristics of six individuals with congenital leptin deficiency before and after leptin treatment
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Context
Whilst severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function.
Objective
The aim of this study was to characterise changes in peripheral metabolism in people with congenital leptin...
Contexts in source publication
Context 1
... characterised the metabolomic response to leptin replacement in severely obese people with congenital leptin deficiency. Fasting metabolome profiles were obtained before and after acute leptin treatment (duration 7 days to one month) in six children, aged between 2 and 18 years, with homozygous loss-of-function mutations in the leptin gene (LEP) ( Table 1). Of the six individuals, five were leptin naïve, whereas the eldest (individual A, previously reported in [6] ) had previously undergone a prolonged period of leptin replacement which had been suspended six months prior to our study following the onset of autoantibody-mediated leptin resistance. ...Context 2
... the six individuals, five were leptin naïve, whereas the eldest (individual A, previously reported in [6] ) had previously undergone a prolonged period of leptin replacement which had been suspended six months prior to our study following the onset of autoantibody-mediated leptin resistance. Weight loss after acute leptin treatment was minimal, and did not exceed 3% baseline weight in any individual (Table 1). The metabolome included quantification of over 600 metabolites, divided into seven "super-pathways" (368 lipid species, 170 amino acid derivatives, 35 nucleotide metabolites, 34 peptides, 23 cofactors and vitamins, 21 carbohydrates and 10 TCA cycle intermediates). ...Context 3
... contrast, leptin treatment was associated with a class-wide increase in levels of sphingomyelin ( Fig 1F; Table S2 [21] ), the most abundant of the sphingolipid species, whilst there was no consistent effect on ceramide metabolites, synthesized by sphingomyelin hydrolysis (Table S1 [21] ). Levels of sphingosine, and A c c e p t e d M a n u s c r i p t related metabolites dihydrosphingosine (sphinganine) and sphingosine-1-phosphate, which are key sphingolipid precursor subunits, decreased although they did not achieve nominal significance (Table S1 [21] ). These observations suggest that leptin may promote the mobilisation of FAs from glycerophospholipids as energy substrate, whilst conserving or even promoting the synthesis of sphingomyelins. ...Similar publications
Background:
Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism with reduced expression of genes governing metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α regulates the expression of branched-chain amino acid (BCAA...
Introduction
Traumatic brain injury (TBI) induces a cascade of cellular alterations that are responsible for evolving secondary brain injuries. Changes in brain structure and function after TBI may occur in concert with dysbiosis and altered amino acid fermentation in the gut. Therefore, we hypothesized that subacute plasma amino acid levels could...
Salt stress negatively affects rice growth, development and yield. Metabolic adjustments contribute to the adaptation of rice under salt stress. Branched‐chain amino acids (BCAA) are three essential amino acids that cannot be synthesized by humans or animals. However, little is known about the role of BCAA in response to salt stress in plants.
Here...
Protein-restricted diets promote health and longevity in many species. While the precise components of a protein-restricted diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of protein restriction can be attributed to reduced dietary levels of the branched-chain amino acids (...
Purpose
White adipose tissue (WAT) has positive effects on peripheral metabolism parameters and liver energy metabolism. This study aimed to explain the pharmacological mechanism of Qushi Huayu (QSHY) granules in the treatment of nonalcoholic fatty liver disease (NALFD) mice based on branched-chain amino acid (BCAA) catabolism and WAT browning.
Pa...
Citations
... In contrast, the rare cases of monogenic forms of obesity, are mainly caused by biallelic mutations in a single gene, usually in the leptin-melanocortin satiety pathway, and are characterized by vary severe, early-onset obesity, usually with evident hyperphagia, and in some cases associated to other metabolic comorbidities and influencing growth pattern even in the first years of life (Handakas et al., 2022). Several metabolomic studies have been performed in childhood obesity, comprehensively characterizing the metabolic alterations in these conditions, as well as in animal models of leptin resistance thus exploring the effect of the impairment of the leptin-POMC satiety pathway (Pietiläinen et al., 2007;Mastrangelo et al., 2016;Martos-Moreno et al., 2017;Rauschert et al., 2017;Kim et al., 2019;Lawler et al., 2020;Rupérez et al., 2020;Sanz-Fernandez et al., 2020). However, the pathogenic role of heterozygous rare sequence variants in the genes of the leptinmelanocortin pathway (Le Collen et al., 2023), as in other genes relevant for central energy and glucose homeostasis is under discussion (Trang and Grant, 2023). ...
Introduction: Obesity results from an interplay between genetic predisposition and environmental factors such as diet, physical activity, culture, and socioeconomic status. Personalized treatments for obesity would be optimal, thus necessitating the identification of individual characteristics to improve the effectiveness of therapies. For example, genetic impairment of the leptin-melanocortin pathway can result in rare cases of severe early-onset obesity. Metabolomics has the potential to distinguish between a healthy and obese status; however, differentiating subsets of individuals within the obesity spectrum remains challenging. Factor analysis can integrate patient features from diverse sources, allowing an accurate subclassification of individuals.
Methods: This study presents a workflow to identify metabotypes, particularly when routine clinical studies fail in patient categorization. 110 children with obesity (BMI > +2 SDS) genotyped for nine genes involved in the leptin-melanocortin pathway (CPE, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, and SIM1) and two glutamate receptor genes (GRM7 and GRIK1) were studied; 55 harboring heterozygous rare sequence variants and 55 with no variants. Anthropometric and routine clinical laboratory data were collected, and serum samples processed for untargeted metabolomic analysis using GC-q-MS and CE-TOF-MS and reversed-phase U(H)PLC-QTOF-MS/MS in positive and negative ionization modes. Following signal processing and multialignment, multivariate and univariate statistical analyses were applied to evaluate the genetic trait association with metabolomics data and clinical and routine laboratory features.
Results and Discussion: Neither the presence of a heterozygous rare sequence variant nor clinical/routine laboratory features determined subgroups in the metabolomics data. To identify metabolomic subtypes, we applied Factor Analysis, by constructing a composite matrix from the five analytical platforms. Six factors were discovered and three different metabotypes. Subtle but neat differences in the circulating lipids, as well as in insulin sensitivity could be established, which opens the possibility to personalize the treatment according to the patients categorization into such obesity subtypes. Metabotyping in clinical contexts poses challenges due to the influence of various uncontrolled variables on metabolic phenotypes. However, this strategy reveals the potential to identify subsets of patients with similar clinical diagnoses but different metabolic conditions. This approach underscores the broader applicability of Factor Analysis in metabotyping across diverse clinical scenarios.
... Leptin (ob/ob) or leptin receptor (db/db) deficient mice and humans developed pronounced hyperphagia and obesity, suggesting leptin is a key player in the control of feeding and energy balance (Zhang et al., 1994;Montague et al., 1997;Cohen et al., 2001). Remarkably, multiple clinical studies have conclusively demonstrated the efficacy of leptin in the amelioration of obesity linked to congenital leptin insufficiency (Kilpeläinen et al., 2016;Dallner et al., 2019;Lawler et al., 2020;Hanssen et al., 2023;Saeed et al., 2023). Intracerebroventricular (ICV) administration of leptin into ob/ob mice or re-expression of leptin receptor in the CNS of db/db mice can fully reverse the corresponding ...
Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin’s action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.
... Leptin is secreted by adipocytes and strongly inhibits feeding and increased energy expenditure mainly through receptors in the hypothalamus, and its inaction is thought to be important in the etiology of obesity [153][154][155][156][157]. Despite accumulating evidence that leptin plays an important role in periodontal diseases, the mechanism by which it promotes periodontitis development is unknown. ...
The periodontal ligament is located between the bone (alveolar bone) and the cementum of the tooth, and it is connected by tough fibers called Sharpey’s fibers. To maintain healthy teeth, the foundation supporting the teeth must be healthy. Periodontal diseases, also known as tooth loss, cause the alveolar bone to dissolve. The alveolar bone, similar to the bones in other body parts, is repeatedly resorbed by osteoclasts and renewed by osteogenic cells. This means that an old bone is constantly being resorbed and replaced by a new bone. In periodontal diseases, the alveolar bone around the teeth is absorbed, and as the disease progresses, the alveolar bone shrinks gradually. In most cases, the resorbed alveolar bone does not return to its original form even after periodontal disease is cured. Gum covers the tooth surface so that it matches the shape of the resorbed alveolar bone, exposing more of the tooth surface than before, making the teeth look longer, leaving gaps between the teeth, and in some cases causing teeth to sting. Previously, the only treatment for periodontal diseases was to stop the disease from progressing further before the teeth fell out, and restoration to the original condition was almost impossible. However, a treatment method that can help in the regeneration of the supporting tissues of the teeth destroyed by periodontal diseases and the restoration of the teeth to their original healthy state as much as possible is introduced. Recently, with improvements in implant material properties, implant therapy has become an indispensable treatment method in dentistry and an important prosthetic option. Treatment methods and techniques, which are mainly based on experience, have gradually accumulated scientific evidence, and the number of indications for treatment has increased. The development of bone augmentation methods has contributed remarkably to the expansion of indications, and this has been made possible by various advances in materials science. The induced pluripotent stem cell (iPS) cell technology for regenerating periodontal tissues, including alveolar bone, is expected to be applied in the treatment of diseases, such as tooth loss and periodontitis. This review focuses on the alveolar bone and describes clinical practice, techniques, and the latest basic research.
... Given that this was a pilot and exploratory study, p-values were not corrected for multiple testing. While the methods we utilized to measure adipokines and incretins have been used in numerous recent studies [92][93][94][95][96][97], mass spectrometry would provide higher specificity [98][99][100]. Other limits were the study restriction of only females with mild to moderate curve severity and the lack of post-prandial assessments. ...
Adolescent idiopathic scoliosis (AIS) is a three-dimensional malformation of the spine of unknown cause that develops between 10 and 18 years old and affects 2–3% of adolescents, mostly girls. It has been reported that girls with AIS have a taller stature, lower body mass index (BMI), and bone mineral density (BMD) than their peers, but the causes remain unexplained. Energy metabolism discrepancies, including alterations in adipokine and incretin circulatory levels, could influence these parameters and contribute to disease pathophysiology. This pilot study aims to compare the anthropometry, BMD, and metabolic profile of 19 AIS girls to 19 age-matched healthy controls. Collected data include participants' fasting metabolic profile, anthropometry (measurements and DXA scan), nutritional intake, and physical activity level. AIS girls (14.8 ± 1.7 years, Cobb angle 27 ± 10°), compared to controls (14.8 ± 2.1 years), were leaner (BMI-for-age z-score ± SD: −0.59 ± 0.81 vs. 0.09 ± 1.11, p = 0.016; fat percentage: 24.4 ± 5.9 vs. 29.2 ± 7.2%, p = 0.036), had lower BMD (total body without head z-score ± SD: −0.6 ± 0.83 vs. 0.23 ± 0.98, p = 0.038; femoral neck z-score: −0.54 ± 1.20 vs. 0.59 ± 1.59, p = 0.043), but their height was similar. AIS girls had higher adiponectin levels [56 (9–287) vs. 32 (7–74) ug/mL, p = 0.005] and lower leptin/adiponectin ratio [0.042 (0.005–0.320) vs. 0.258 (0.024–1.053), p = 0.005]. AIS participants with a Cobb angle superior to 25° had higher resistin levels compared to controls [98.2 (12.8–287.2) vs. 32.1 (6.6–73.8), p = 0.0013]. This pilot study suggests that adipokines are implicated in AIS development and/or progression, but more work is needed to confirm their role in the disease.
... Currently, the commonly used analytical platforms for metabolomics refer to liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), and enzyme assays (13). In recent years, ultra-high performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) has displayed obvious advantages in sensitivity, rapidness, efficiency, and cost-saving, which increasingly applied in human plasma metabolomics research (12,14). For example, a previous study demonstrated the high accuracy of UPLC-MS/MS in detecting serum concentration in SCZ (12). ...
Schizophrenia (SCZ) acts as a complex and burdensome disease, in which the functional outcome can be validly predicted by cognitive impairment, as one of the core features. However, there still lack considerable markers of cognitive deficits in SCZ. Based on metabolomics, it is expected to identify different metabolic characteristics of SCZ with cognitive impairment. In the present study, 17 SCZ patients with cognitive impairment (CI), 17 matched SCZ patients with cognitive normal (CN), and 20 healthy control subjects (HC) were recruited, whose plasma metabolites were measured using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The result of metabolic profiling indicated the identification of 46 differentially expressed metabolites between HC, CN, and CI groups, with 7 differentially expressed metabolites between CN and CI groups. Four differential metabolites (imidazolepropionic acid, Homoserine, and Aspartic acid) were repeatedly found in both screenings, by which the formed biomarker panel could discriminate SCZ with cognitive impairment from matched patients (AUC = 0.974) and health control (AUC = 0.841), respectively. Several significant metabolic pathways were highlighted in pathway analysis, involving Alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, and Citrate cycle (TCA cycle). In this study, several differentially expressed metabolites were identified in SCZ with cognitive impairment, providing novel insights into clinical treatment strategies.
... 34 Similar changes in these lipid classes were also observed in a study measuring metabolomic profiles over the course of a 10-day fast 33 and following leptin replacement therapy among individuals with congenital deficiency. 35 Intriguingly, both studies of acute and prolonged CR also note similar reductions of plasmalogen phosphatidylethanolamines and not phosphatidylcholines associated with fasting. ...
Background
Intermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.
Methods
We conducted a randomised-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Participants were randomised to 1 of 3 diets: 1) a control diet, in which the participant received 100% of his or her calorie needs 7 days per week, 2) a daily CR diet, in which the participant received 78% of his or her calorie needs 7 days per week, or 3) an intermittent CR diet, in which the participant received 100% of his or her calorie needs on 5 days per week and 25% of his or her calorie needs 2 days per week (i.e., a “5:2” style diet). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD3⁺;CD4⁺ (CD4⁺) and CD3⁺;CD4⁻ (as a proxy for CD8⁺) T cell subsets including effector memory, central memory, and naïve cells.
Findings
31 (86%) completed the trial. Over time, individuals randomised to intermittent CR had significant reductions in effector memory (for CD4⁻EM: -3.82%; 95%CI: -7.44, -0.21; for CD4⁻: -6.96%; 95%CI: -11.96, -1.97) and Th1 subsets (-4.26%; 95% CI: -7.11, -1.40) and proportional increases in naïve subsets (for CD4⁻: 10.11%; 95%CI: 3.30, 16.92%). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naïve T cell subsets.
Interpretation
In people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets and certain biologically-relevant lipid markers.
Funding
National MS Society, NIH, Johns Hopkins Catalyst Award.
... Moreover, several SNPs were found to target miRNAs linked with adipogenesis and lipid metabolism (28). Clinical studies in patients with obesity have revealed that mutations in leptin, pro-opiomelanocortin (POMC), and melanocortin 4 receptor (MC4R) are positively associated with hyperphagia, hyperinsulinemia, and excessive adiposity (29)(30)(31)(32)(33)(34). Accordingly, several research efforts have focused on developing therapies against obesity by targeting these genes, mainly to enhance satiety and reduce energy intake. ...
Obesity has become a global epidemic, and it is a major risk factor for other metabolic disorders such as type 2 diabetes and cardiometabolic disease. Accumulating evidence indicates that there is sex-specific metabolic protection and disease susceptibility. For instance, in both clinical and experimental studies, males are more likely to develop obesity, insulin resistance, and diabetes. In line with this, males tend to have more visceral white adipose tissue (WAT) and less brown adipose tissue (BAT) thermogenic activity, both leading to an increased incidence of metabolic disorders. This female-specific fat distribution is partially mediated by sex hormone estrogens. Specifically, hypothalamic estrogen signaling plays a vital role in regulating WAT distribution, WAT beiging, and BAT thermogenesis. These regulatory effects on adipose tissue metabolism are primarily mediated by the activation of estrogen receptor alpha (ERα) in neurons, which interacts with hormones and adipokines such as leptin, ghrelin, and insulin. This review discusses the contribution of adipose tissue dysfunction to obesity and the role of hypothalamic estrogen signaling in preventing metabolic diseases with a particular focus on the VMH, the central regulator of energy expenditure and glucose homeostasis.
... These metabolic dysfunctions gradually develop with time. Currently, several omics approaches, such as metabolomics analysis of blood and tissue samples, have been applied to gain new insights into the pathophysiology of metabolic diseases and to evaluate the severity of metabolic disorders and the effectiveness of treatment [2][3][4]. Metabolomics is an emerging tool for investigating small molecules and biochemical metabolites. Profiles of metabolites provide essential information regarding an individual's health status. ...
Decline of ovarian function in menopausal women increases metabolic disease risk. Curcuma comosa extract and its major compound, (3 R )-1,7-diphenyl-(4 E ,6 E )-4,6-heptadien-3-ol (DPHD), improved estrogen-deficient ovariectomized (OVX) rat metabolic disturbances. However, information on their effects on metabolites is limited. Here, we investigated the impacts of C . comosa ethanol extract and DPHD on 12-week-old OVX rat metabolic disturbances, emphasizing the less hydrophobic metabolites. Metabolomics analysis of OVX rat serum showed a marked increase compared to sham-operated rat (SHAM) in levels of lysophosphatidylcholines (lysoPCs), particularly lysoPC (18:0) and lysoPC (16:0), and of arachidonic acid (AA), metabolites associated with inflammation. OVX rat elevated lysoPCs and AA levels reverted to SHAM levels following treatments with C . comosa ethanol extract and DPHD. Overall, our studies demonstrate the effect of C . comosa extract in ameliorating the metabolic disturbances caused by ovariectomy, and the elevated levels of bioactive lipid metabolites, lysoPCs and AA, may serve as potential biomarkers of menopausal metabolic disturbances.
... Адипоциты выделяют лептин в кровь прямо пропорционально массе ЖТ и нутритивному статусу больного [64,65]. Фактором, определяющим уровень экспрессии лептина, является размер адипоцита -важная детерминанта синтеза лептина: крупные жировые клетки содержат гораздо большее количество гормона, чем мелкие адипоциты [66, Т а б л и ц а 2 / T a b l e 2 ]. ...
... Таким образом, лептин является как индикатором энергетических запасов, так и медиатором энергетического баланса [68]. Полученные нами данные свидетельствуют о том, что выраженное ожирение у детей тесно связано с гиперлептинемией и резистентностью к лептину -состоянием, при котором лептин не подавляет аппетит, увеличивает расход энергии и регулирует метаболизм гликолипидов [64,69,70]. При этом лептин не выполняет своей функции метаболического гормона, ограничивающего избыточную прибавку в весе при гиперлептинемии и лептинорезистентности в связи с нарушением передачи сигналов лептина в вентромедиальном ядре гипоталамуса [71][72][73]. ...
... Возможно, при ожирении селективная лептинорезистентность является ключевым регулятором, определяющим избыточное накопление ЖТ. Нужно учитывать также, что лептин широко задействован в дополнительных регуляторных функциях, включая модулирующие эффекты на врождённый и адаптивный иммунный ответ [64,65]. Лептин оказывает множественное вегетативное и сердечно-сосудистое действие, включая симпатическую активацию, увеличение эндотелиального NO и ангиогенез. ...
Introduction. Constitutionally exogenous obesity (CEO) belongs to a number of significant medical and social problems of the modern world, assumes epidemic proportions and leads among alimentary-dependent pathology in children. The aim of the work was to determine changes in indicators of endothelial dysfunction (ED) in children of different age with obesity of various severity. Materials and methods. One hundred twenty six children aged of 6 to 17 years were comprehensively examined, data on changes in the serum content of ED mediators in CEOs grade 1-3 were presented by quantitative determination of nitric oxide, endothelin-1, leptin, homocysteine, intercellular adhesion molecules and vascular cell adhesion-1, tissue-type plasminogen activator inhibitor antigen, Willebrand factor and his antigen. Results. The regularities of changes in the concentrations of these compounds in the blood depending on the age of patients and the degree of obesity, which reflect the functional state of the endothelial system and can serve as criteria for the severity of ED requiring adequate and timely correction in children, have been established. Conclusion. Indicators of endothelial dysfunction can serve as criteria for its severity, their detection will allow optimizing early diagnosis and determining the amount of timely therapy.
... With accumulating new evidence on the involvement of bile acids in a growing number of human physiological and pathological conditions, there is renewed interest in improving the measuring techniques for various bile acids in different biological samples. Ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) is a new method developed in the last 20 years (Sun et al., 2019;Hu et al., 2020;Lawler et al., 2020). Using the theory and principle of HPLC, UPLC has improved and innovated a number of chromatographic technologies, including small particle fillers, very low system volumes, and rapid detection methods, which increase the flux, sensitivity, and chromatographic peak capacity of analysis . ...
Bile acid is a derivative of cholinergic acid (steroidal parent nucleus) that plays an important role in digestion, absorption, and metabolism. In recent years, bile acids have been identified as signaling molecules that regulate self-metabolism, lipid metabolism, energy balance, and glucose metabolism. The detection of fine changes in bile acids caused by metabolism, disease, or individual differences has become a research hotspot. At present, there are many related techniques, such as enzyme analysis, immunoassays, and chromatography, that are used for bile acid detection. These methods have been applied in clinical practice and laboratory research to varying degrees. However, mainstream detection technology is constantly updated and replaced with the passage of time, proffering new detection technologies. Previously, gas chromatography (GS) and gas chromatography-mass spectrometry (GC-MS) were the most commonly used for bile acid detection. In recent years, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has developed rapidly and has gradually become the mainstream bile acid sample separation and detection technology. In this review, the basic principles, development and progress of technology, applicability, advantages, and disadvantages of various detection techniques are discussed and the changes in bile acids caused by related diseases are summarized.
