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Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the thyroid gland to produce and release thyroid hormones, primarily thyroxine and triiodothyronine. These hormones are key players in body-brain communication, influencing various physiological processes, including the regulation of metabolism (both peripheral and central effects), feedback mechanisms, and lipid metabolism. Recently, the increasing incidence of abnormal lipid metabolism has highlighted the link between thyroid function and lipid metabolism. Evidence suggests that TSH can affect all bodily systems through body-brain communication, playing a crucial role in growth, development, and the regulation of various physiological systems. Lipids serve dual purposes: they are involved in energy storage and metabolism, and they act as vital signaling molecules in numerous cellular activities, maintaining overall human health or contributing to various diseases. This article reviews the role of TSH in regulating lipid metabolism via body-brain crosstalk, focusing on its implications for common lipid metabolism disorders such as obesity, atherosclerosis, nonalcoholic fatty liver disease, neuropsychiatric disorders (including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and depression), and cerebrovascular disorders such as stroke., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients., Methods: This study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals., Results: Our findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing "dual changes" including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection., Conclusions: Our study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease., (© 2024. The Author(s).)

Objective: This study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats., Methods: A total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology., Results: In comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role., Conclusion: This study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) stands as a leading cause of severe visual impairment and blindness among the elderly globally. As a multifactorial disease, AMD's pathogenesis is influenced by genetic, environmental, and age-related factors, with lipid metabolism abnormalities and complement system dysregulation playing critical roles. This review delves into recent advancements in understanding the intricate interaction between these two crucial pathways, highlighting their contribution to the disease's progression through chronic inflammation, drusen formation, and retinal pigment epithelium dysfunction. Importantly, emerging evidence points to dysregulated lipid profiles, particularly alterations in high-density lipoprotein levels, oxidized lipid deposits, and intracellular lipofuscin accumulation, as exacerbating factors that enhance complement activation and subsequently amplify tissue damage in AMD. Furthermore, genetic studies have revealed significant associations between AMD and specific genes involved in lipid transport and complement regulation, shedding light on disease susceptibility and underlying mechanisms. The review further explores the clinical implications of these findings, advocating for a novel therapeutic approach that integrates lipid metabolism modulators with complement inhibitors. By concurrently targeting these pathways, the dual-targeted approach holds promise in significantly improving outcomes for AMD patients, heralding a new horizon in AMD management and treatment.

It is not clear if fat oxidation is attenuated at higher exercise intensities, when exercising with a small muscle mass, and therefore, we studied leg fat oxidation during graded one-leg exercise. Ten males (age: 27 ± 2 years, body mass: 82 ± 3 kg, BMI: 24 ± 1 kg m -2 , V̇O 2max : 49 ± 2 mL min -1  kg -1 ) performed one-leg exercise at 25% of maximal workload (W max ) for 30 min, followed by 120-min exercise at 55% W max with the contralateral leg, and finally 30-min exercise at 85% W max with the first leg. Blood was sampled from an artery and both femoral veins, and blood flow was determined using Doppler ultrasound. Muscle biopsies were obtained before and after 30 min at each workload. One-way RM ANOVA was applied to determine the impact of exercise intensity. Data are expressed as mean ± SEM. From rest through exercise average blood flow (0.4 ± 0.1, 2.1 ± 0.1, 2.6 ± 0.2, 3.7 ± 0.2 L min -1 ) and oxygen uptake across the leg (0.03 ± 0.01, 0.23 ± 0.02, 0.35 ± 0.03, 0.53 ± 0.04 L min -1 ) increased with exercise intensity (p < 0.001). Leg RQ (0.76 ± 0.04, 0.86 ± 0.02,0.87 ± 0.01, 0.92 ± 0.01, p < 0.001), leg plasma FA uptake (2 ± 2, 46 ± 8,83 ± 9, 114 ± 16 μmol min -1 ; p < 0.001) and rate of leg fat oxidation (0.016 ± 0.005, 0.062 ± 0.012, 0.075 ± 0.011, 0.084 ± 0.018 g min -1 , p < 0.007) increased with exercise intensity. Muscle-free carnitine content was unchanged from rest at 25% W max and decreased after 30 min exercise at 55% and 85% W max (17.4 ± 1.6, 16.6 ± 0.7, 14.5 ± 1.2, 10.5 ± 1.0 mmol/kg dry muscle, respectively; p < 0.006). During incremental one-leg exercise, the rate of leg fat oxidation was not attenuated with increasing exercise intensity, probably due to an insufficient muscle metabolic stress response., (© 2024 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease., (© 2024. The Author(s).)

Neurodegenerative diseases (NDDs) are a series of disorders characterized by the progressive loss of specific neurons, leading to cognitive and locomotor impairment. NDDs affect millions of patients worldwide but lack effective treatments. Dysregulation of lipids, particularly the accumulation of lipid droplets (LDs), is strongly implicated in the pathogenesis of NDDs. How LDs contribute to the occurrence and development of NDDs, and their potential as therapeutic targets remain to be addressed. In present review, we first introduce the processes of LDs formation, transportation and degradation. We then highlight how the accumulation of LDs contributes to the pathogenesis of NDDs in a cell type-specific manner. Moreover, we discuss currently available methods for detecting LDs and elaborate on LDs-based therapeutic strategies for NDDs. Lastly, we identify gaps that need to be filled to better leverage LD-based theranostics in NDDs and other diseases. We hope this review could shed light on the role of LDs in NDDs and facilitate the development of novel therapeutic strategies for NDDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese db/db and control db/+ mice were fasted for 24 h twice a week for 10 wk. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in db/db or db/+ mice. After IF, db/db mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control db/+ mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility, and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control db/+ mice but not in obese db/db mice. After IF, db/db mice also had lower serum β-hydroxybutyrate than control db/+ mice. Ten weeks of IF decreased adipocyte size in visceral adipose tissue of control db/+ mice, but this IF regimen did not change adipocyte size in obese db/db mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes. NEW & NOTEWORTHY We show that a 5:2 intermittent fasting regimen can increase lipid oxidation without altering body mass in lean mice. Therefore, repeated intermittent fasting can increase metabolic flexibility without the need for (or prior to) weight loss. Intermittent fasting did not increase lipid oxidation in mice with obesity and type 2 diabetes, highlighting that obesity and/or type 2 diabetes limit changes in metabolic flexibility and mitigate increased fatty acid oxidation without weight loss during intermittent fasting.

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia, and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increase susceptibility to oxidative stress, lipotoxicity, and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions and of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis, and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.

We examined the lipid profiles in the aqueous humor (AH) of myopic patients to identify differences and investigate the relationships among dissertating lipids. Additionally, we assessed spherical equivalents and axial lengths to explore the pathogenesis of myopia. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was employed to qualitatively and quantitatively analyze the lipid composition of samples from myopic patients with axial lengths <26 mm (Group A) and >28 mm (Group B). Differences in lipid profiles between the two groups were determined using univariate and multivariate analyses. Receiver operator characteristic (ROC) curves were used to identify discriminating lipids. Spearman correlation analysis explored the associations between lipid concentrations and biometric parameters. Three hundred and nine lipids across 21 lipid classes have been identified in this study. Five lipids showed significant differences between Group B and Group A (VIP >1, P < 0.05): BMP (20:3/22:3), PG (22:1/24:0), PS (14:1/22:4), TG (44:2)&#95;FA18:2, and TG (55:3)&#95;FA18:1. The area under the curve (AUC) for these lipids was >0.75. Notably, the concentrations of BMP (20:3/22:3), PS (14:1/22:4), and TG (55:3)&#95;FA18:1 were correlated with spherical equivalents, while BMP (20:3/22:3) and PS (14:1/22:4) correlated with axial lengths. Our study identified five differential lipids in myopic patients, with three showing significant correlations with the degree of myopia. These findings enhance our understanding of myopia pathogenesis through lipidomic alterations, emphasizing changes in cell membrane composition and function, energy metabolism and storage, and pathways involving inflammation, peroxisome proliferator-activated receptors (PPAR), and metabolic processes related to phosphatidylserine, phosphatidylglycerol, triglycerides, polyunsaturated fatty acids, and cholesterol., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: To investigate the associations of the Dietary Approaches to Stop Hypertension (DASH) score with subcutaneous (SAT) and visceral (VAT) adipose tissue volume and hepatic lipid content (HLC) in people with diabetes and to examine whether changes in the DASH diet were associated with changes in these outcomes., Methods: In total, 335 participants with recent-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) from the German Diabetes Study were included in the cross-sectional analysis, and 111 participants in the analysis of changes during the 5-year follow-up. Associations between the DASH score and VAT, SAT and HLC and their changes were investigated using multivariable linear regression models by diabetes type. The proportion mediated by changes in potential mediators was determined using mediation analysis., Results: A higher baseline DASH score was associated with lower HLC, especially in people with T2D (per 5 points: -1.5% [-2.7%; -0.3%]). Over 5 years, a 5-point increase in the DASH score was associated with decreased VAT in people with T2D (-514 [-800; -228] cm 3 ). Similar, but imprecise, associations were observed for VAT changes in people with T1D (-403 [-861; 55] cm 3 ) and for HLC in people with T2D (-1.3% [-2.8%; 0.3%]). Body mass index and waist circumference changes explained 8%-48% of the associations between DASH and VAT changes in both groups. In people with T2D, adipose tissue insulin resistance index (Adipo-IR) changes explained 47% of the association between DASH and HLC changes., Conclusions: A shift to a DASH-like diet was associated with favourable VAT and HLC changes, which were partly explained by changes in anthropometric measures and Adipo-IR., (© 2024 John Wiley & Sons Ltd.)

Men generally favor carbohydrate metabolism, while women lean towards lipid metabolism, resulting in significant sex-based differences in energy oxidation across various metabolic states such as fasting and feeding. These differences are influenced by body composition and inherent metabolic fluxes, including increased lipolysis rates in women. However, understanding how sex influences organ-specific metabolism and systemic manifestations remains incomplete. To address these gaps, we developed a sex-specific, whole-body metabolic model for feeding and fasting scenarios in healthy young adults. Our model integrates organ metabolism with whole-body responses to mixed meals, particularly high-carbohydrate and high-fat meals. Our predictions suggest that differences in liver and adipose tissue nutrient storage and oxidation patterns drive systemic metabolic disparities. We propose that sex differences in fasting hepatic glucose output may result from the different handling of free fatty acids, glycerol, and glycogen. We identified a metabolic pathway, possibly more prevalent in female livers, redirecting lipids towards carbohydrate metabolism to support hepatic glucose production. This mechanism is facilitated by the TG-FFA cycle between adipose tissue and the liver. Incorporating sex-specific data into multi-scale frameworks offers insights into how sex modulates human metabolism., Competing Interests: Declaration of competing interest None Declared, (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the clinical and endocrine risk factors for pregnancy loss in women with abnormal glucose/lipid metabolism and a history of pregnancy loss, and to develop a predictive model to assess the risk of pregnancy loss in these women's subsequent pregnancies., Methods: Patients with a history of pregnancy loss who had abnormal glucose/lipid metabolism were retrospectively included in this study, and their pre-pregnancy baseline and clinical characteristics were collected. A predictive nomogram was constructed based on the results of the multivariable logistic regression model analysis, and its calibration and discriminatory capabilities were evaluated. The internal validation was then performed and the net benefits were assessed by the clinical decision curve., Results: The predictive model was eventually incorporated eight variables, including maternal age, previous pregnancy losses, anticardiolipin antibody (aCL) IgG, aCL IgM, thyroid peroxidase antibody, complement 4, free thyroxine and total cholesterol. The area under the curve (AUC) of the nomogram was 0.709, and Chi-square value and P value of the Hosmer-Lemeshow test were 12.786 and 0.119, respectively, indicating that the nomogram had a satisfactory calibration and discriminatory performance. The validation cohort showed a similar result for the discrimination of the nomogram (AUC = 0.715). The clinical decision curve demonstrated the nomogram had good positive net benefits., Conclusions: This is the first study to predict the risks of subsequent pregnancy loss in women with abnormal glucose/lipid metabolism and history of pregnancy loss using pre-pregnancy clinical and endocrine parameters. This predictive nomogram may provide clinicians assistance to personalize the management of subsequent pregnancies in these patients., (© 2024. The Author(s).)

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet. In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion. We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m 6 A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI. By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage., Competing Interests: Declaration of competing interest The authors declare no competing financial and/or non-financial interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Continuous (chronic or sub-chronic) alcohol consumption induces a metabolic byproduct known as ketone bodies, and the accumulation of ketones leads to a life-threatening syndrome called alcoholic ketoacidosis. However, the mechanism underlining the physiological effects of ketone accumulation in alcoholic liver disease (ALD) is still in its infancy. Here, we discovered that mitochondrial acetyl-CoA accumulation was diverted into the ketogenesis pathway in ethanol-fed mice and ethanol-exposed hepatocytes. Unexpectedly, global protein lysine β-hydroxybutyrylation (Kbhb) was induced in response to increased ketogenesis-derived β-hydroxybutyrate (BHB) levels both in hepatocytes and in livers of mice. Focusing on the solute carrier family (SLCs), we found that SLC25A5 presented obvious Kbhb at lysine residues 147 and 166. Kbhb modifications at these two lysine residues stabilized SLC25A5 expression by blocking ubiquitin-proteasome pathway. Subsequent mutation analysis revealed that Kbhb of SLC25A5 at K147 and K166 had site-specific regulatory roles by increasing peroxisome proliferator activated receptor gamma (PPARγ) expression, which further promoting lipogenesis. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2), a rate-limiting enzyme for BHB production, was profoundly induced by ethanol exposure, and knockout of Hmgcs2 with CRISPR/Cas9 attenuated SLC25A5 Kbhb. Together, our study demonstrated a widespread Kbhb landscape under ethanol exposure and clarified a physiological effect of Kbhb modification on liver lipid accumulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Spotted stem borer, Chilo partellus, undergoes larval diapause (hibernation and aestivation), and depends on the food reserve accumulated during feeding stage for its survival. Lipids are the primary source of energy during diapause, and essential for different cellular, biochemical and physiological functions. However, there is no information on lipid and lipophilic compound contents during different stages of hibernation, aestivation and nondiapause in C. partellus. Thus, we compared the concentration and composition of lipids in pre-diapause, diapause and post-diapause stages of hibernation and aestivation with nondiapause stages of C. partellus. The studies revealed significant differences in total lipids and various lipophilic compounds during different stages of diapause as compared to nondiapause C. partellus. The total lipids were significantly lower during diapause stage of aestivation and hibernation as compared to nondiapause larvae. Further, the linoleic acid, Methyl 3-methoxytetradecanoate, and l-(+)-Ascorbic acid 2,6-dihexadecanoate were significantly lower, and oleic and palmitoleic acids greater during pre-diapause and diapause stages of hibernation and aestivation as compared to nondiapause larvae. The cholesterol content was significantly greater during pre-diapause stage of hibernation, and diapause and post-diapause stages of aestivation as compared to nondiapause stages. The unsaturation ratio was significantly higher in the pre-diapause and diapause stages and lower in post-diapause stage of aestivation than the hibernation and nondiapause states. This study provides insights on differential lipid profiles during different phases of diapause, which could be useful for further understanding biochemical and physiological cross-talk, and develop target-specific technologies for the management of C. partellus., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate if diurnal oscillation in maximal fat oxidation (MFO) and substrate oxidation rates during exercise exists in subjects with metabolic syndrome (MetS)., Methods: In a randomized crossover design, 14 MetS patients were assigned to two graded exercise tests conditions performed in the morning (between 7:00 and 9:00 a.m) and in the afternoon (between 4:00 and 5:00 p.m). MFO was defined as the highest absolute value of fat oxidation obtained from the average of last 2-min stages during an indirect calorimetry test., Results: MFO increased by 20.6% from morning to afternoon (p = 0.0002, Cohen's d = 0.52). There was a significant time of day, (p < 0.0001, η 2 p = 0.76) and intensity effect (p = 0.002, η 2 p = 0.32) in fat oxidation (Fatox) rates indicating that Fatox was higher in the afternoon than in the morning., Conclusion: Our study extends previous findings on the existence of diurnal variation in maximal fat oxidation to MetS patients, highlighting the afternoon as a more favorable time for fat utilization during exercise. These findings have practical implications for optimizing training timing in MetS patients., Trial Registration Number: PACTR202306776991260., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nuclear receptor NR4A1 is a key factor in glycolipid metabolism and steroidogenesis, while lipid droplets serve as crucial dynamic organelles for lipid metabolism in luteal cells. To investigate the effects of NR4A1 on lipid droplet metabolism and progesterone (P4) synthesis in goat corpus luteum in vitro, luteal cells from the middle-cyclic corpus luteum were isolated and treated with Cytosporone B (CSNB, an agonist) or siRNA of NR4A1. Results showed that both low (1 μM) and high (50 μM) concentrations of CSNB promoted lipid droplet accumulation, while NR4A1 knockdown reduced lipid droplet content. CSNB increased while siNR4A1 decreased total cholesterol content; however, CSNB and siNR4A1 did not change triglyceride content. CSNB increased the expression of perilipins at mRNA and protein levels, also increased LDLR, SCARB1, SREBFs, and HMGCR mRNA abundance. Treatment with siNR4A1 revealed opposite results of CSNB, except for HMCGR and SREBF2. For steroidogenesis, 1 μM CSNB increased, but 50 μM CSNB inhibited P4 synthesis, NR4A1 knockdown also reduced the P4 level. Further analysis demonstrated that 1 μM CSNB increased the protein levels of StAR, HSD3B, and P-HSL, while 50 μM CSNB decreased StAR, HSD3B, and CYP11A1 protein levels. Moreover, 50 μM CSNB impaired active mitochondria, reduced the BCL2, and increased DRP1, Caspase 3, and cleaved-Caspase 3 protein levels. siNR4A1 consistently downregulated the P-HSL/HSL ratio and the steroidogenic protein levels. In conclusion, NR4A1-mediated lipid droplets are involved in the regulation of progesterone synthesis in goat luteal cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Microglia are important innate immune cells in the brain, and a rich diversity of subtypes has recently been discovered that expand beyond the traditional classification of traditional M1 (pro-inflammatory) and M2 (anti-inflammatory) classifications. Intracerebral hemorrhage (ICH) is a devastating form of stroke, and the understanding of its later-stage pathological mechanisms remains incomplete. In this study, through the analysis of single-cell transcripts from mice brains 14 days post-ICH, three disease-associated expression patterns of microglia were identified. These include a lipid metabolism and phagocytosis phenotype reminiscent of Disease-Associated Microglia (DAM) initially discovered in Alzheimer's disease models, a phenotype associated with angiogenesis, and a relatively independent phenotype similar to the pro-inflammatory M1 state. These findings were further validated through immunofluorescence in both mouse and human specimens. In addition, analysis of single-cell transcripts from mice brains 3 days post-ICH suggested that microglia involved in lipid metabolism and phagocytosis likely emerge from early proliferating populations. Given the distinct origins and phenotypic characteristics of pro-inflammatory and reparative microglia, interventions targeting these cells hold the potential to modulate the delicate balance between injury and repair during the pathophysiological process of ICH, highlighting a pivotal direction for future therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Metabolic syndrome (MetS) is a group of metabolic abnormalities that identifies people at risk for diabetes and cardiovascular disease. MetS is characterized by lipid disorders, and non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) are thought to be the common hepatic and renal manifestations of MetS following abnormal lipid metabolism. This paper reviews the molecular mechanisms of lipid deposition in NAFLD and DKD, highlighting the commonalities and differences in lipid metabolic pathways in NAFLD and DKD. Hepatic and renal steatosis is the result of lipid acquisition exceeding lipid processing, i.e., fatty acid uptake and lipid regeneration exceed fatty acid oxidation and export. This process is directly regulated by the interactions of nuclear receptors, transporter proteins and transcription factors, whereas pathways such as oxidative stress, autophagy, cellular pyroptosis and gut flora are also key regulatory hubs for lipid metabolic homeostasis but act slightly differently in the liver and kidney. Such insights based on liver-kidney similarities and differences offer potential options for improved treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

This study investigates the intricate mechanisms underlying the correlation between elevated consumption of harmful fats and the onset of kidney malignancies. The rise in global obesity rates has been accompanied by an increased prevalence of renal cancers, prompting an exploration into the molecular pathways and biological processes linking these phenomena. Through an extensive review of current literature and clinical studies, we identify potential key factors contributing to the carcinogenic influence of harmful fats on renal tissues. Our analysis highlights the role of adipose tissue-derived factors, inflammatory mediators, and lipid metabolism dysregulation in fostering a microenvironment conducive to renal tumorigenesis. Furthermore, we delve into the impact of harmful fats on signaling pathways associated with cell proliferation, apoptosis evasion, and angiogenesis within the renal parenchyma. This review underscores the importance of elucidating the molecular intricacies linking lipid metabolism and kidney malignancies, offering a foundation for future research and the development of targeted preventive and therapeutic interventions. The findings discussed herein contribute to our understanding of the complex relationship between lipid mediators and renal cancer, providing a basis for public health strategies aimed at mitigating the impact of harmful fats on kidney health., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodríguez-Vázquez, Aranda-Torrecillas, López-Sancho, Castellano and Tena-Sempere.)

Background: Cognitive impairment is a core symptom of schizophrenia. Metabolic abnormalities impact cognition, and although the influence of blood lipids on cognition has been documented, it remains unclear. We conducted a small cross-sectional study to investigate the relationship between blood lipids and cognition in patients with stable-phase schizophrenia. Using Olink proteomics, we explored the potential mechanisms through which blood lipids might affect cognition from an inflammatory perspective., Methods: A total of 107 patients with stable-phase schizophrenia and cognitive impairment were strictly included. Comprehensive data collection included basic patient information, blood glucose, blood lipids, and body mass index. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB). After controlling for confounding factors, we identified differential metabolic indicators between patients with mild and severe cognitive impairment and conducted correlation and regression analyses. Furthermore, we matched two small sample groups of patients with lipid metabolism abnormalities and used Olink proteomics to analyze inflammation-related differential proteins, aiming to further explore the association between lipid metabolism abnormalities and cognition., Results: The proportion of patients with severe cognitive impairment (SCI) was 34.58%. Compared to patients with mild cognitive impairment (MCI), those with SCI performed worse in the Attention/Alertness (t = 2.668, p = 0.009) and Working Memory (t = 2.496, p = 0.014) cognitive dimensions. Blood lipid metabolism indicators were correlated with cognitive function, specifically showing that higher levels of TG (r = -0.447, p < 0.001), TC (r = -0.307, p = 0.002), and LDL-C (r = -0.607, p < 0.001) were associated with poorer overall cognitive function. Further regression analysis indicated that TG (OR = 5.578, P = 0.003) and LDL-C (OR = 5.425, P = 0.001) may be risk factors for exacerbating cognitive impairment in individuals with stable-phase schizophrenia. Proteomics analysis revealed that, compared to individuals with stable-phase schizophrenia and normal lipid metabolism, those with hyperlipidemia had elevated levels of 10 inflammatory proteins and decreased levels of 2 inflammatory proteins in plasma, with these changes correlating with cognitive function. The differential proteins were primarily involved in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway., Conclusion: Blood lipids are associated with cognitive function in individuals with stable-phase schizophrenia, with higher levels of TG, TC, and LDL-C correlating with poorer overall cognitive performance. TG and LDL-C may be risk factors for exacerbating cognitive impairment in these patients. From an inflammatory perspective, lipid metabolism abnormalities might influence cognition by activating or downregulating related proteins, or through pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, and IL-17 signaling pathway., (© 2024. The Author(s).)

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: The study aims to examine the changing trajectory characteristics of dynamic functional network connectivity (dFNC) and its correlation with lipid metabolism-related factors across the Alzheimer's disease (AD) spectrum populations., Methods: Data from 242 AD spectrum subjects, including biological, neuroimaging, and general cognition, were obtained from the Alzheimer's Disease Neuroimaging Initiative for this cross-sectional study. The study utilized a sliding-window approach to assess whole-brain dFNC, investigating group differences and associations with biological and cognitive factors. Abnormal dFNC was used in the classification of AD spectrum populations by support vector machine. Mediation analysis was performed to explore the relationships between lipid-related indicators, dFNC, cerebrospinal fluid (CSF) biomarkers, and cognitive performance., Results: Significant group difference concerning were observed in relation to APOE-ε4 status, CSF biomarkers, and cognitive scores. Two reoccurring connectivity states were identified: state-1 characterized by frequent but weak connections, and state-II characterized by less frequent but strong connections. Pre-AD subjects exhibited a preference for spending more time in state-I, whereas AD patients tended remain in state-II for longer periods. Group difference in dFNC was primarily found between AD and non-AD participants within each state. The dFNC of state-I yielded strong power to distinguish AD from other groups compared with state-II. APOE-ε4 + , high polygenic score, and high serum lipid group were strongly associated with network disruption between association cortex system and sensory cortex system that characterized elevation of cognitive function, which may suggest a compensatory mechanism of dFNC in state-I, whereas differential connections of state-II mediated the relationships between APOE-ε4 genotype and CSF biomarkers, and cognitive indicators., Conclusion: The dysfunction of dFNC temporal-spatial patterns and increased cognition in individuals with APOE-ε4, high polygenic score, and higher serum lipid levels shed light on the lipid-related mechanisms of dynamic network reorganization in AD., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Multiomics approaches have significantly aided the identification of molecular signatures in complex neuropsychiatric disorders. Lipidomics, one of the newest additions in the -omics family, sheds light on lipid profiles and is an emerging methodological tool to study schizophrenia pathobiology, as lipid dysregulation has been repeatedly observed in schizophrenia. In this review, we performed a detailed literature search for lipidomics studies in schizophrenia. Following elaborate inclusion/exclusion criteria, we focused on human studies in schizophrenia and schizophrenia-related diagnoses in brain and blood specimens, including serum plasma, platelets and red blood cells. Eighteen studies fulfilled our inclusion criteria, of which five were conducted in the brain, 12 in peripheral material and one in both. Here, we first provide background on lipidomics and the main lipid categories addressed, review in detail the included literature and look for common lipidomics patterns in brain and the periphery that emerge from these studies. Furthermore, we highlight current limitations in schizophrenia lipidomics research and underline the need for following up on lipidomics results with complementary molecular approaches., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims/hypothesis: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD., Methods: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions., Results: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes., Conclusions/interpretation: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although metabolic disturbance is a characteristic of diabetic cardiomyopathy (DbCM), the detailed pathogenesis of DbCM remains unknown., Methods: We used a heart transplantation (HTx) cohort to explore the effect of diabetes mellitus on heart failure (HF) progression dependent of myocardium. Microscopic and ultramicroscopic pathology were used to depict the pathological features of human myocardium of DbCM. We performed targeted metabolomics to characterize the metabolic phenotype of human DbCM. Transcriptomics data were analyzed and weighted gene co-expression network analysis was performed to explore the potential upstream regulator for metabolic remodeling of DbCM. In vivo and in vitro experiments were further conducted to demonstrate the therapeutic effects and molecular mechanisms., Results: DbCM promoted the progression of HF and increased death or HF-rehospitalization after HTx. Lipid accumulation and mitochondrial fission were the obvious pathological features of DbCM myocardium. The concentrations of C14:0-CoA and C16:1-CoA were significantly increased in the myocardium, and they were positively correlated with the accelerated HF progression and RCAN1 expression in DbCM patients. Knockdown of RCAN1 improved cardiac dysfunction, lipid accumulation, and mitochondrial fission in db/db mice. In vitro studies showed that RCAN1 knockdown improved mitochondrial dysfunction in DbCM cardiomyocytes via the RCAN1-p-Drp1 Ser 616 axis., Conclusions: Diabetes is associated with faster progression of HF and causes poor prognosis after HTx, accompanied by metabolic remodeling in the myocardium. Accumulation of long chain acyl-CoA in the myocardium is the metabolic hallmark of human DbCM and is associated with more rapid disease progression for DbCM patients. Upregulation of RCAN1 in the myocardium is associated with the metabolic signatures of DbCM and RCAN1 is a potential therapeutic target for DbCM., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Gestational Diabetes Mellitus (GDM) presents a significant health concern globally, necessitating a comprehensive understanding of its metabolic intricacies for effective management. MicroRNAs (miRNAs) have emerged as pivotal regulators in GDM pathogenesis, influencing glucose metabolism, insulin signaling, and lipid homeostasis during pregnancy. Dysregulated miRNA expression, both upregulated and downregulated, contributes to GDM-associated metabolic abnormalities. Ethnic and temporal variations in miRNA expression underscore the multifaceted nature of GDM susceptibility. This review examines the dysregulation of miRNAs in GDM and their regulatory functions in metabolic disorders. We discuss the involvement of specific miRNAs in modulating key pathways implicated in GDM pathogenesis, such as glucose metabolism, insulin signaling, and lipid homeostasis. Furthermore, we explore the potential diagnostic and therapeutic implications of miRNAs in GDM management, highlighting the promise of miRNA-based interventions for mitigating the adverse consequences of GDM on maternal and offspring health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LDs) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. For example, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and the proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Our analyses showed reductions in LD volume, area, and perimeter in aged samples in comparison to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for the mitochondria interacting with LDs. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology with mitochondrial function, metabolism, and bioactivity in aged BAT., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

The aim of the study was to investigate the relationship between ooplasm morphology, lipid content, glucose-6-phosphate dehydrogenase activity (G6PDH) and maturation potential of domestic cat oocytes. Cumulus-oocyte complexes were classified according to ooplasm morphology: evenly dark (dCOC), heterogeneous/mosaic (hCOC), or light/transparent (lCOC), however only dCOCs are thought to be the best-quality, the remaining ones are usually rejected, therefore little is known about their intracellular properties. Lipid droplets (LDs) were visualized and quantified using Oil Red O. G6PDH activity was assessed before in vitro maturation (IVM), using the brilliant cresyl blue (BCB) test. IVM-control oocytes underwent IVM without BCB staining. The dCOCs and hCOCs had different patterns of LD spatial distribution, but similar amounts of lipid, although this tended towards being lower in hCOCs. Low G6PDH activity (BCB+) was observed in 74 %, 60 % and 24 % (P < 0.01) of dCOCs, hCOCs, and lCOCs, respectively. Significantly more BCB+ /oocytes than BCB-/oocytes reached the metaphase II stage in all groups. The maturation rate of BCB+ /hCOCs was higher than that of IVM/hCOC-controls (40 % v.s. 20 %, P < 0.001), and was comparable to that of BCB+ /dCOCs (54 %; P > 0.05). lCOCs were the smallest (P < 0.01), contained fewer (P < 0.01) lipids than dCOCs or hCOCs, and displayed reduced maturational potential. Overall, LD content and distribution, as well as G6PDH activity, in cat oocytes were strongly associated with ooplasm morphology and oocyte maturational competence. Deeper understanding of the intrinsic properties of oocytes with different ooplasm morphology using the domestic cat model, may be particularly important in the context of the conservation of endangered felids., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2024 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Citrus fruits are widely consumed for their nutritional and health benefits. They belong to the Rutaceae and have many varieties, such as sweet orange (Citrus sinensis), which is the most popular. Citrus fruits are rich in water (>80%), dietary fiber, and vitamins. They also contain bioactive components, which may modulate energy metabolism and lipid oxidation through various mechanisms. These mechanisms include stimulating β3-adrenergic receptors, increasing mitochondrial biogenesis and thermogenesis, activating AMP kinase and peroxisome proliferator-activated receptor-gamma coactivator-1α pathways, inhibiting lipogenesis and lipid accumulation, and inducing browning of white adipose tissue. This review summarizes the mechanisms and outcomes of citrus fruits and their metabolites on energy metabolism and body weight in different experimental models. The literature was searched for in vitro and in vivo animal and human studies that investigated the effects of citrus consumption on energy expenditure, thermogenesis, adipogenesis, and lipid accumulation. Citrus fruits and their metabolites have shown promising effects on energy metabolism and lipid oxidation in in vitro and in vivo animal studies. However, the evidence from human studies is limited and inconsistent. Possible reasons for the discrepancy are briefly discussed, and knowledge gaps and research needs are identified for future studies. Citrus fruits may have beneficial effects on energy metabolism and body weight, but more rigorous and well-designed human trials are needed to confirm their efficacy and safety., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

It is imperative to optimise health and healthspan across the lifespan. The accumulation of reactive oxygen species (ROS) has been implicated in the hallmarks of ageing and inhibiting ROS production can potentially delay ageing whilst increasing healthy longevity. Lipids and lipid mediators (derivatives of lipids) are becoming increasingly recognized as central molecule in tissue and cellular function and are susceptible to peroxidation; hence linked with ageing. Lipid classes implicated in the ageing process include sterols, glycerophospholipids, sphingolipids and the oxidation products of polyunsaturated fatty acids but these are not yet translated into the clinic. Further mechanistic studies are required for the understanding of lipid classes in the ageing process. Lipidomics, the system level characterisation of lipid species with respect to metabolism and function, might provide a significant and useful biological age profiling tool through longitudinal studies. Lipid profiles in different ages among healthy individuals could be harnessed as lipid biomarkers of healthy ageing with potential integration for the development of lipid-based ageing clock (lipid clock). The potential of a lipid clock includes the prediction of future morbidity or mortality, which will promote precision and healthy longevity medicine., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Owing to the global obesity epidemic, understanding the regulatory mechanisms of glucose and lipid metabolism has become increasingly important. The dopaminergic system, including dopamine, dopamine receptors, dopamine transporters, and other components, is involved in numerous physiological and pathological processes. However, the mechanism of action of the dopaminergic system in glucose and lipid metabolism is poorly understood. In this review, we examine the role of the dopaminergic system in glucose and lipid metabolism., Results: The dopaminergic system regulates glucose and lipid metabolism through several mechanisms. It regulates various activities at the central level, including appetite control and decision-making, which contribute to regulating body weight and energy metabolism. In the pituitary gland, dopamine inhibits prolactin production and promotes insulin secretion through dopamine receptor 2. Furthermore, it can influence various physiological components in the peripheral system, such as pancreatic β cells, glucagon-like peptide-1, adipocytes, hepatocytes, and muscle, by regulating insulin and glucagon secretion, glucose uptake and use, and fatty acid metabolism., Conclusions: The role of dopamine in regulating glucose and lipid metabolism has significant implications for the physiology and pathogenesis of disease. The potential therapeutic value of dopamine lies in its effects on metabolic disorders., (© 2024 The Obesity Society.)

Background: With aging, white adipose tissue (WAT) undergoes distribution change and browning inhibition, which could be attenuated by exercise. Adipokine chemerin exerts roles in the above changes of WAT, and our previous studies demonstrated the effect of decreased chemerin on exercise-induced improvement of glucose and lipid metabolism in high fat diet (HFD) feeding male mice, so this study is to clarify whether chemerin's effects on glucose and lipid metabolism are associated with the distribution and browning of WAT., Methods: After diet and exercise interventions, body weight and adipose tissue contents in different depots of male mice were weighed, body composition and energy metabolism parameters were determined by Echo MRI Body Composition Analyzer and metabolic cage, respectively. The levels of serum adiponectin and leptin were detected by ELISA, and the protein levels of PGC-1α, UCP1, adiponectin and leptin in WAT were measured by Western blot., Results: Chemerin knockout exacerbated HFD-induced weight gain, upregulated the increases of visceral and subcutaneous WAT (vWAT and sWAT, especial in sWAT), and inhibited WAT browning, but improved blood lipid. Exercise reduced the body weight and WAT distribution, increased sWAT browning and further improved blood lipid in aged HFD male mice, which were abrogated by chemerin knockout. Detrimental alterations of leptin, adiponectin and adiponectin/leptin ratio were discovered in the serum and WAT of aged HFD chemerin(-/-) mice; and exercise-induced beneficial changes in these adipokines were blocked by chemerin knockout., Conclusion: Chemerin influences blood lipid of aged male mice under HFD and exercise states through regulating the distribution and browning of WAT, which might be related to the changes of adiponectin, leptin and adiponectin/leptin ratio., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans αS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3K αS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased αS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3K mice with LIPE null mice, which attenuated motor deficits in male LIPE +/- knockdown (LKD)-3K mice. Heterozygous LIPE reduction was associated with an improved αS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which αS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease., Competing Interests: Declaration of Competing Interest DJS is a director and consultant of Prothena Biosciences and ad hoc consultant to Esai. The other authors declare no competing financial or non-financial interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer's disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome., Competing Interests: Declaration of interests P.D.C. is a co-founder and CTO of SeqBiome Ltd. J.T.G. has received research funding from BBSRC, MRC, Cancer Research UK, the British Heart Foundation, Clasado Biosciences, Lucozade Ribena Suntory, Arla Foods Ingredients, the Cosun Nutrition Center, and the Fruit Juice Science Center; is a scientific advisory board member to ZOE; and has completed paid consultancy for 6d Sports Nutrition, The Dairy Council, PepsiCo, Violicom Medical, Tour Racing Ltd., and SVGC. J.A.B. is an investigator on research grants funded by BBSRC, MRC, the British Heart Foundation, Rare Disease Foundation, EU Hydration Institute, GlaxoSmithKline, Nestlé, Lucozade Ribena Suntory, Arla Foods, Cosun Nutrition Center, American Academy of Sleep Medicine Foundation, and Salus Optima (L3M Technologies Ltd.); has completed paid consultancy for PepsiCo, Kellogg’s, SVGC, and Salus Optima (L3M Technologies Ltd.); is Company Director of Metabolic Solutions Ltd.; receives an annual honorarium as a member of the academic advisory board for the International Olympic Committee Diploma in Sports Nutrition; and receives an annual stipend as Editor-in-Chief of International Journal of Sport Nutrition & Exercise Metabolism., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated., Methods: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases., Results: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase., Conclusions: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies., (© 2024. The Author(s).)

Context: Alterations in the lipid metabolism are linked to metabolic disorders such as insulin resistance (IR), obesity and type 2 diabetes (T2D). Regular exercise, particularly combined training (CT), is a well-known nonpharmacological treatment that combines aerobic (AT) and resistance (RT) training benefits. However, it is unclear whether moderate-intensity exercise without dietary intervention induces changes in lipid metabolism to promote a "healthy lipidome.", Objective: The study aimed to investigate the effect of 16 weeks of CT on plasma and white adipose tissue in both sexes, middle-aged individuals with normal weight, obesity (OB), and T2D using an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) untargeted lipidomics approach., Methods: Body composition, maximum oxygen consumption (VO2max), strength, and biochemical markers were evaluated before and after the control/training period and correlated with lipid changes. CT consisted of 8 to 10 RT exercises, followed by 35 minutes of AT (45%-70% VO2max), 3 times a week for 16 weeks., Results: The CT significantly reduced the levels of saturated and monounsaturated fatty acid side-chains (SFA/MUFA) in sphingolipids, glycerolipids (GL) and glycerophospholipids (GP) as well as reducing fat mass, circumferences and IR. Increased levels of polyunsaturated fatty acids in GPs and GLs were also observed, along with increased fat-free mass, VO2 max, and strength (all P < .05) after training., Conclusion: Our study revealed that 16 weeks of moderate-intensity CT remodeled the lipid metabolism in OB, and T2D individuals, even without dietary intervention, establishing a link between exercise-modulated lipid markers and mechanisms that reduce IR and obesity-related comorbidities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Sex is key variable influencing body composition and substrate utilization. At rest, females maintain greater adiposity than males and resist the mobilization of fat. Males maintain greater lean muscle mass and mobilize fat readily. Determining the mechanisms that direct these sex-dependent effects is important for both reproductive and metabolic health. Here, we highlight the fundamental importance of sex in shaping metabolic physiology and assess growing evidence that the hepatokine fibroblast growth factor-21 (FGF21) plays a mechanistic role to facilitate sex-dependent responses to a changing nutritional environment. First, we examine the importance of sex in modulating body composition and substrate utilization. We summarize new data that point toward sex-biased effects of pharmacologic FGF21 administration on these endpoints. When energy is not limited, metabolic responses to FGF21 mirror broader sex differences; FGF21-treated males conserve lean mass at the expense of increased lipid catabolism, whereas FGF21-treated females conserve fat mass at the expense of reduced lean mass. Next, we examine the importance of sex in modulating the endogenous secretion of FGF21 in response to changing macronutrient and energy availability. During the resting state when energy is not limited, macronutrient imbalance increases the secretion of FGF21 more so in males than females. When energy is limited, the effect of sex on both the secretion of FGF21 and its metabolic actions may be reversed. Altogether, we argue that a growing literature supports FGF21 as a plausible mechanism contributing to the sex-dependent mobilization vs preservation of lipid storage and highlight the need for further research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: Hypothyroidism has been proposed as a potential contributor to steatotic liver disease (SLD), but existing data shows conflicting results in euthyroid subjects. Therefore, we investigated the association between thyroid function and intrahepatic lipids (IHLs) during a 36-month randomized controlled trial evaluating a diet known to reduce liver fat., Design: 502 eligible subjects (aged 50-80 years, ≥1 risk factor for unhealthy aging) were randomly assigned to either follow a diet rich in unsaturated fatty acids, plant protein, and fiber (intervention group, IG), or dietary recommendations of the German Nutrition Society (control group, CG)., Methods: Serum levels of thyroid hormones (THs) as well as IHLs, defined via magnetic resonance spectroscopy, were measured within an euthyroid subgroup without significant alcohol consumption at baseline (n = 332) and after 12 months (n = 243). A ratio of T3/T4 was used to assess whole-body deiodinase activity. Estimates of glucose and lipid metabolism were analyzed., Results: Only fT3 and T3/T4 ratios showed a significant positive correlation with IHL at baseline. We observed a significant decline in fT3, T3, fT3/fT4 ratio, and T3/T4 ratio in CG and IG after 12 months without significant differences between groups. TSH, fT4, and T4 remained stable. A larger improvement of IHL during dietary intervention was seen in those subjects with a lower decline in T3 concentrations., Conclusions: Altered TH balance indicates a possible compensatory upregulation of whole-body TH activity in subjects with increased liver fat. This might be also relevant during the improvement of hepatic steatosis., Competing Interests: Conflict of Interest: MSB, THN, CW, JM, TS, DP, EKW, JS, and KM declare no conflict of interest. The lab of FT has received funding from Gilead, MSD, and AstraZeneca. FT has served as a consultant for Novo Nordisk, AstraZeneca, Gilead, Abbvie, Alnylam, BMS, Intercept, Falk, Inventiva, MSD, Pfizer, GSK, Novartis and Sanofi. LPB was employed by Charité-Universitätsmedizin Berlin during the conduct of the study, but as of the 1st of August 2023 is employed by Novo Nordisk., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Women are generally less active than men; therefore, the search for an attractive form of physical activity that benefits women's health is underway. This study aimed to investigate the influence of a 24-week physical activity program on body composition and indices of carbohydrates and lipid metabolism in sedentary, healthy women. The study comprised 18 female volunteers (mean age 35.0 ± 5.3 years). Dietary intake was assessed using a standardized seven-day food record. Before entering the program and after completing it, each participant's body composition and indices of glycolipid metabolism were measured. Insulin resistance indexes were calculated based on the obtained data. After the physical activity program, significant decreases in body mass and composition, BMI, waist circumference, percentage of fat content, and fat mass were found. Moreover, there was a significant decrease in glucose, insulin, triglycerides (TG), and resistin concentrations, as well as in the mean values of HOMA-IR and HOMA-AD. A substantial increase in adiponectin levels was also found. To conclude, the combined endurance-resistance physical activity program had a beneficial effect on body mass and composition and improved carbohydrate and lipid metabolism in normal-weight, healthy women. Therefore, we recommend this activity to sedentary young women to prevent obesity and metabolic disorders.

In this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN., (© 2024. The Author(s).)

Anxiety disorders constitute a spectrum of psychological conditions affecting millions of individuals worldwide, imposing a significant health burden. Historically, the development of anxiolytic medications has been largely focused on neurotransmitter function and modulation. However, in recent years, neurolipids emerged as a prime target for understanding psychiatric pathogenesis and developing novel medications. Neurolipids influence various neural activities such as neurotransmission and cellular functioning, as well as maintaining cell membrane integrity. Therefore, this review aims to elucidate the alterations in neurolipids associated with an anxious mental state and explore their potential as targets of novel anxiolytic medications. Existing evidence tentatively associates dysregulated neurolipid levels with the etiopathology of anxiety disorders. Notably, preclinical investigations suggest that several neurolipids, including endocannabinoids and polyunsaturated fatty acids, may hold promise as potential pharmacological targets. Overall, the current literature tentatively suggests the involvement of lipids in the pathogenesis of anxiety disorders, hinting at potential prospects for future pharmacological interventions., Competing Interests: Disclosure statement During the preparation of this work, the authors used ChatGPT to refine the flow and structure of some sentences. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied., Objectives: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures., Methods: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel., Results: In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD., Conclusions: Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid (EET)-producing enzyme, promotes insulin sensitivity, and Cyp2c44-/- mice show hepatic insulin resistance. Because insulin resistance leads to hepatic lipid accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic lipid metabolism. Standard chow diet (SCD)-fed male Cyp2c44-/- mice had significantly decreased EET levels and increased hepatic and plasma lipid levels compared with wild-type mice. We showed increased hepatic plasma membrane localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids and diacylglycerol (DAG) levels. Cyp2c44-/- mice had impaired glucose tolerance and increased hepatic plasma membrane-associated PKCδ and phosphorylated IRS-1, two negative regulators of insulin signaling. Surprisingly, SCD and high-fat diet (HFD)-fed Cyp2c44-/- mice had similar glucose tolerance and hepatic plasma membrane PKCδ levels, suggesting that SCD-fed Cyp2c44-/- mice have reached their maximal glucose intolerance. Inhibition of PKCδ resulted in decreased IRS-1 serine phosphorylation and improved insulin-mediated signaling in Cyp2c44-/- hepatocytes. Finally, Cyp2c44-/- HFD-fed mice treated with the analog EET-A showed decreased hepatic plasma membrane FATP2 and PCKδ levels with improved glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with concomitant decreased EET levels leads to increased hepatic FATP2 plasma membrane localization, DAG accumulation, and PKCδ-mediated attenuation of insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by linking it to insulin signaling., (© 2024 by the American Diabetes Association.)

Glucose and lipid metabolic disorders (GLMDs), such as diabetes, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver disease, and obesity, are significant public health issues that negatively impact human health. The endoplasmic reticulum (ER) plays a crucial role at the cellular level for lipid and sterol biosynthesis, intracellular calcium storage, and protein post-translational modifications. Imbalance and dysfunction of the ER can affect glucose and lipid metabolism. As an essential trace element, selenium contributes to various human physiological functions mainly through 25 types of selenoproteins (SELENOs). At least 10 SELENOs, with experimental and/or computational evidence, are predominantly found on the ER membrane or within its lumen. Two iodothyronine deiodinases (DIOs), DIO1 and DIO2, regulate the thyroid hormone deiodination in the thyroid and some external thyroid tissues, influencing glucose and lipid metabolism. Most of the other eight members maintain redox homeostasis in the ER. Especially, SELENOF, SELENOM, and SELENOS are involved in unfolded protein responses; SELENOI catalyzes phosphatidylethanolamine synthesis; SELENOK, SELENON, and SELENOT participate in calcium homeostasis regulation; and the biological significance of thioredoxin reductase 3 in the ER remains unexplored despite its established function in the thioredoxin system. This review examines recent research advances regarding ER SELENOs in GLMDs and aims to provide insights on ER-related pathology through SELENOs regulation., Competing Interests: Declaration of competing interest All authors have no commercial or financial ties that could be seen as a conflict of interest in the study we did. So there were no conflicts of interest in the study., (Copyright © 2024 Elsevier B.V. All rights reserved.)