Metabolism: clinical and experimental最新文献

{"title":"Metabolic dysfunction-associated steatotic liver disease and urinary system cancers: Mere coincidence or reason for concern?","authors":"Fernando Bril ,&nbsp;Alicia Elbert","doi":"10.1016/j.metabol.2024.156066","DOIUrl":"10.1016/j.metabol.2024.156066","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease characterized by insulin resistance and lipotoxicity. Its association with type 2 diabetes, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma are well described. However, the association of MASLD and extra-hepatic cancers has received significantly less attention. This narrative review will summarize the conflicting evidence regarding the association between MASLD and cancers of the urinary system, including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma. It will explore potential mechanisms that could be responsible for a higher risk of urinary system cancers in patients with MASLD. We hope that our comprehensive assessment of the literature will help the readers to better interpret the available evidence.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156066"},"PeriodicalIF":10.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering organoids-on-chips for drug testing and evaluation","authors":"Hui Wang ,&nbsp;Wan Zhu ,&nbsp;Cong Xu ,&nbsp;Wentao Su ,&nbsp;Zhongyu Li","doi":"10.1016/j.metabol.2024.156065","DOIUrl":"10.1016/j.metabol.2024.156065","url":null,"abstract":"<div><div>Organoids-on-chips is an emerging innovative integration of stem cell-derived organoids with advanced organ-on-chip technology, providing a novel platform for the in vitro construction of biomimetic micro-physiological systems. The synergistic merger transcends the limitations of traditional drug screening and safety assessment methodologies, such as 2D cell cultures and animal models. In this review, we examine the prevailing challenges and prerequisites of preclinical models utilized for drug screening and safety evaluations. We highlighted the salient features and merits of organoids-on-chip, elucidating their capability to authentically replicate human physiology, thereby addressing contemporary impediments. We comprehensively overviewed the recent endeavors where organoids-on-chips have been harnessed for drug screening and safety assessment and delved into potential opportunities and challenges for evolving sophisticated, near-physiological organoids-on-chips. Based on current achievements, we further discuss how to enhance the practicality of organoids-on-chips and accelerate the translation from preclinical to clinical stages in healthcare and industry by utilizing multidisciplinary convergent innovation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156065"},"PeriodicalIF":10.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum lipidomic signatures in patients with varying histological severity of metabolic-dysfunction associated steatotic liver disease","authors":"Sneha Muralidharan ,&nbsp;Jonathan W.J. Lee ,&nbsp;Yee Siang Lim ,&nbsp;Mark Muthiah ,&nbsp;Eunice Tan ,&nbsp;Deniz Demicioglu ,&nbsp;Asim Shabbir ,&nbsp;Wai Mun Loo ,&nbsp;Chieh Sian Koo ,&nbsp;Yin Mei Lee ,&nbsp;Gwyneth Soon ,&nbsp;Aileen Wee ,&nbsp;Nur Halisah ,&nbsp;Sakinah Abbas ,&nbsp;Shanshan Ji ,&nbsp;Alexander Triebl ,&nbsp;Bo Burla ,&nbsp;Hiromi W.L. Koh ,&nbsp;Yun Shen Chan ,&nbsp;Mei Chin Lee ,&nbsp;Yock Young Dan","doi":"10.1016/j.metabol.2024.156063","DOIUrl":"10.1016/j.metabol.2024.156063","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Patients with metabolic associated steatohepatitis (MASH) with fibrosis are at greatest risk of liver and cardiovascular complications. To identify such at-risk MASLD patients, physicians are still reliant on invasive liver biopsies. This study aimed to identify circulating lipidomic signatures to better identify patients with MASH in a multi-ethnic Asian cohort.</div></div><div><h3>Approach &amp; results</h3><div>A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures for MASLD, at-risk MASH and advanced fibrosis were identified. 210 lipids showed significant differences for varying histological subtypes of MASLD. Majority of these lipids were associated with liver steatosis (198/210). We identified a panel of 13 lipids associated with lobular inflammation, ballooning and significant fibrosis. Of note, dihexosylceramides were novel markers for significant fibrosis. Using the serum lipidome alone, we could stratify patients with MASLD (AUROC 0.863), as well as those with at-risk MASH (AUROC 0.912) and advanced fibrosis (AUROC 0.95). The lipidomic at-risk MASH predictor, using 14 markers, was independently validated (n = 105) with AUROC 0.76.</div></div><div><h3>Conclusions</h3><div>The dynamic shift in serum lipid profile was associated with progressive histological stages of MASLD, providing surrogate markers for distinguishing stages of MASLD as well as identifying novel pathways in the pathogenesis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156063"},"PeriodicalIF":10.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis","authors":"Francesca Pontanari ,&nbsp;Hadrien Demagny ,&nbsp;Adrien Faure ,&nbsp;Xiaoxu Li ,&nbsp;Giorgia Benegiamo ,&nbsp;Antoine Jalil ,&nbsp;Alessia Perino ,&nbsp;Johan Auwerx ,&nbsp;Kristina Schoonjans","doi":"10.1016/j.metabol.2024.156061","DOIUrl":"10.1016/j.metabol.2024.156061","url":null,"abstract":"<div><div>Several laboratories, including ours, have employed the <em>Slc25a47</em>^{tm1c(EUCOMM)Hmgu} mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the <em>Slc25a47-Wars1</em> locus in hepatocytes are primarily driven by the unexpected downregulation of <em>Wars1</em>, the cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to <em>Slc25a47</em>. While the downregulation of <em>Wars1</em> predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPR^mt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of <em>Slc25a47</em> and <em>Wars1</em> in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156061"},"PeriodicalIF":10.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Body weight control via protein kinase CK2: diet-induced obesity counteracted by pharmacological targeting","authors":"Laura M. Buchwald ,&nbsp;Ditte Neess ,&nbsp;Daniel Hansen ,&nbsp;Thomas K. Doktor ,&nbsp;Vignesh Ramesh ,&nbsp;Lasse B. Steffensen ,&nbsp;Blagoy Blagoev ,&nbsp;David W. Litchfield ,&nbsp;Brage S. Andresen ,&nbsp;Kim Ravnskjaer ,&nbsp;Nils J. Færgeman ,&nbsp;Barbara Guerra","doi":"10.1016/j.metabol.2024.156060","DOIUrl":"10.1016/j.metabol.2024.156060","url":null,"abstract":"<div><h3>Background</h3><div>Protein kinase CK2 is a highly conserved enzyme implicated in the pathogenesis of various human illnesses including obesity. Despite compelling evidence for the involvement of this kinase in the pathophysiology of obesity, the molecular mechanisms by which CK2 might regulate fat metabolism are still poorly understood.</div></div><div><h3>Methods and results</h3><div>In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both <em>in vitro</em> and <em>in vivo</em> approaches using mouse pre-adipocytes and a mouse model of diet-induced obesity. We show that pharmacological inhibition of CK2 by CX-4945 results in premature upregulation of p27^KIP1 preventing the progression of cells into mature adipocytes by arresting their development at the intermediate phase of adipogenic differentiation. Consistent with this, we show that <em>in vivo</em>, CK2 regulates the expression levels and ERK-mediated phosphorylation of C/EBPβ, which is one of the earliest transcription factors responsive to adipogenic stimuli. Furthermore, we demonstrate the functional implication of CK2 in the expression of late markers of adipogenesis and factors regulating lipogenesis in liver and white adipose tissue. Finally, we show that while mice subjected to high-fat diet increased their body weight, those additionally treated with CX-4945 gained considerably less weight. NMR-based body composition analysis revealed that this is linked to significant differences in body fat mass.</div></div><div><h3>Conclusions</h3><div>Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156060"},"PeriodicalIF":10.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy","authors":"Irem Congur ,&nbsp;Geltrude Mingrone ,&nbsp;Kaomei Guan","doi":"10.1016/j.metabol.2024.156062","DOIUrl":"10.1016/j.metabol.2024.156062","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156062"},"PeriodicalIF":10.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of glycogen in cardiac metabolic stress","authors":"Ke-Fa Xiang ,&nbsp;Jing-jing Wan ,&nbsp;Peng-yuan Wang ,&nbsp;Xia Liu","doi":"10.1016/j.metabol.2024.156059","DOIUrl":"10.1016/j.metabol.2024.156059","url":null,"abstract":"<div><div>Metabolic stress in the myocardium arises from a diverse array of acute and chronic pathophysiological contexts. Glycogen mishandling is a key feature of metabolic stress, while maladaptation in energy-stress situations confers functional deficits. Cardiac glycogen serves as a pivotal reserve for myocardial energy, which is classically described as an energy source and contributes to glucose homeostasis during hypoxia or ischemia. Despite extensive research activity, how glycogen metabolism affects cardiovascular disease remains unclear. In this review, we focus on its regulation across myocardial energy metabolism in response to stress, and its role in metabolism, immunity, and autophagy. We further summarize the cardiovascular-related drugs regulating glycogen metabolism. In this way, we provide current knowledge for the understanding of glycogen metabolism in the myocardium.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156059"},"PeriodicalIF":10.8,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte-specific SLC27A4 deletion ameliorates nonalcoholic fatty liver disease in mice via suppression of phosphatidylcholine-mediated PXR activation","authors":"Chuangpeng Shen ,&nbsp;Zhisen Pan ,&nbsp;Wenmin Xie ,&nbsp;Jian Zhao ,&nbsp;Deyu Miao ,&nbsp;Ling Zhao ,&nbsp;Min Liu ,&nbsp;Yanhua Zhong ,&nbsp;Chong Zhong ,&nbsp;Frank J. Gonzalez ,&nbsp;Wei Wang ,&nbsp;Yong Gao ,&nbsp;Changhui Liu","doi":"10.1016/j.metabol.2024.156054","DOIUrl":"10.1016/j.metabol.2024.156054","url":null,"abstract":"<div><h3>Background</h3><div>The protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood.</div></div><div><h3>Methods</h3><div>Mice with AAV-mediated overexpression of <em>Slc27a4</em> in liver and hepatocytes-specific deletion of <em>Slc27a4</em> were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence.</div></div><div><h3>Results</h3><div>This study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of <em>Slc27a4</em> improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of <em>Slc27a4</em> deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of <em>Slc27a4</em> overexpression on NAFLD development.</div></div><div><h3>Conclusion</h3><div>These results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156054"},"PeriodicalIF":10.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1,25-Dihydroxyvitamin D3 protects against placental inflammation by suppressing NLRP3-mediated IL-1β production via Nrf2 signaling pathway in preeclampsia","authors":"Xueqing Liu ,&nbsp;Xinyu Zhang ,&nbsp;Linlin Ma ,&nbsp;Na Qiang ,&nbsp;Jiao Wang ,&nbsp;Yujia Huang ,&nbsp;Xiaolei Yuan ,&nbsp;Chunmei Lu ,&nbsp;Yang Cao ,&nbsp;Jie Xu","doi":"10.1016/j.metabol.2024.156058","DOIUrl":"10.1016/j.metabol.2024.156058","url":null,"abstract":"<div><h3>Background</h3><div>Maternal vitamin D deficiency is associated with an increased risk of preeclampsia, a potentially life-threatening multi-system disorder specific to human pregnancy. Placental trophoblast dysfunction is a key factor in the development of preeclampsia, and the activation of NOD-like receptor protein 3 (NLRP3) inflammasome may play a crucial role in this process. Previous studies have suggested that vitamin D can exert beneficial effects by suppressing inflammasome activation, but the underlying mechanism has not been fully elucidated. This study aims to explore the protective effects of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on the placenta and to investigate the mechanisms by which 1,25(OH)₂D₃ attenuates NLRP3 inflammasome activation in a rat model of preeclampsia and hypoxia-cultured placental trophoblast cells.</div></div><div><h3>Results</h3><div>Our findings demonstrated that supplementation of rats with 1,25(OH)₂D₃ mitigated placental inflammation and prevented multi-organ dysfunction associated with preeclampsia. Treatment with 1,25(OH)₂D₃ inhibited inflammasome-mediated inflammation in trophoblast cells via its receptor VDR by reducing the expression of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), decreasing IL-1β production, reducing mitochondrial reactive oxygen species generation, and enhancing the expression and enzymatic activity of Cu/Zn-superoxide dismutase (SOD). Mechanistically, 1,25(OH)₂D₃ upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, subsequently suppressing NLRP3-mediated IL-1β overproduction in trophoblast cells.</div></div><div><h3>Conclusions</h3><div>Our study indicates that 1,25(OH)₂D₃ inhibits NLRP3-mediated inflammation in trophoblast cells during preeclampsia by stimulating the Nrf2 signaling pathway and inhibiting oxidative stress.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156058"},"PeriodicalIF":10.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health","authors":"Konstantinos Stefanakis ,&nbsp;Jagriti Upadhyay ,&nbsp;Arantxa Ramirez-Cisneros ,&nbsp;Nihar Patel ,&nbsp;Akshat Sahai ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156056","DOIUrl":"10.1016/j.metabol.2024.156056","url":null,"abstract":"<div><div>Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156056"},"PeriodicalIF":10.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}