Obesity-related Metabolic Dysfunction Research Articles

Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.

To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity.

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

Amlexanox attenuates LPS-induced neuroinflammatory responses in microglial cells via inhibition of NF–κB and STAT3 signaling pathways

Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases.

Gastric Submucosal Fat Accumulation Is Associated with Insulin Resistance in Patients with Obesity

PurposeEctopic fat accumulation plays a significant role in obesity-related metabolic dysfunction, and few studies have reported an association between ectopic gastric fat and metabolic risk factors. We aim to fulfill this need by assessing the degree of gastric submucosal fat accumulation in pathologic sections of 190 sleeve gastrectomy specimens.MethodsStudy patients were divided into two groups (D1 and D2) based on whether fat accumulation exceeded 1/3 of the submucosa of the stomach. Demographic and metabolic risk factors were compared between the two groups. Metabolic risk variables that might be associated with the degree of fat accumulation were screened in the original cohort. After balancing for possible confounders, the robustness of the correlations was assessed using binary and conditional logistic regression analyses.ResultsAll study patients had fat accumulation in the submucosa of the stomach. C-reactive protein (CRP), body mass index (BMI), visceral fat area (VFA), and insulin resistance (IR) were higher in the D2 group than in the D1 group in the original cohort (P < 0.05). Logistic regression analysis showed that BMI and IR may be associated with increased fat accumulation. After balancing variables other than obesity indicators and IR using propensity score matching, BMI and IR remained significantly different between the two groups (P < 0.05). Further analysis of the matched cohort using two logistic regression analyses showed that IR was an independent risk factor for increased fat accumulation.ConclusionThis study indicated that gastric submucosal fat accumulation was prevalent in patients with obesity and was associated with IR.Graphical

Le tissu adipeux dans tous ses états : dernières avancées: The different colours and functions of adipose tissue: what’s new?

Obesity represents a growing global health issue today. Understanding the mechanisms underlying the formation, growth, and function of adipose tissue is crucial in combating this disease and its associated complications, such as type 2 diabetes and cardiovascular diseases. In France, obesity is on the rise, particularly among young adults and children. In this review, we discuss the cellular composition of white adipose tissue, highlighting recent advances in the characterisation of various cell populations. We also explore the metabolic implications of body fat distribution, emphasizing the importance of brown and beige adipose tissues in metabolism regulation. These thermogenic tissues offer significant metabolic benefits, opening up promising opportunities in research and development of therapeutic strategies to address obesity-related metabolic disorders. Furthermore, we discuss the relationship between cellular senescence and obesity-related metabolic dysfunction, along with new research in the field of intercellular communication and mitochondrial recycling. Finally, this review provides a comprehensive overview of recent developments in the understanding of obesity at adipose cells level.© 2023 Société francophone nutrition clinique et métabolisme (SFNCM).Published by Elsevier Masson SAS. All rights reserved.

FGF21 alleviates adipose stem cell senescence via CD90 glycosylation-dependent glucose influx in remodeling healthy white adipose tissue

The senescence of adipose stem cells (ASCs) impairs healthy adipose tissue remodeling, causing metabolic maladaptation to energy surplus. The intrinsic molecular pathways and potential therapy targets for ASC senescence are largely unclear. Here, we showed that visceral ASCs were prone to senescence that was caused by reactive oxygen species (ROS) overload, especially mitochondrial ROS. These senescent ASCs failed to sustain efficient glucose influx, pentose phosphate pathway (PPP) and redox homeostasis. We showed that CD90 silence restricted the glucose uptake by ASCs and thus disrupted their PPP and anti-oxidant system, resulting in ASC senescence. Notably, fibroblast growth factor 21 (FGF21) treatment significantly reduced the senescent phenotypes of ASCs by augmenting CD90 protein via glycosylation, which promoted glucose influx via the AKT-GLUT4 axis and therefore mitigated ROS overload. For diet-induced obese mice, chronic administration of low-dose FGF21 relieved their visceral white adipose tissue (VAT) dysfunction and systemic metabolic disorders. In particular, VAT homeostasis was restored in FGF21-treated obese mice, where ASC repertoire was markedly recovered, accompanied by CD90 elevation and anti-senescent phenotypes in these ASCs. Collectively, we reveal a molecular mechanism of ASC senescence by which CD90 downregulation interferes glucose influx into PPP and redox homeostasis. And we propose a FGF21-based strategy for healthy VAT remodeling, which targets CD90 glycosylation to correct ASC senescence and therefore combat obesity-related metabolic dysfunction.

Soluble RAGE and skeletal muscle tissue RAGE expression profiles in lean and obese young adults across differential aerobic exercise intensities.

Nearly 40% of Americans have obesity and are at increased risk for developing type 2 diabetes. Skeletal muscle is responsible for >80% of insulin-stimulated glucose uptake that is attenuated by the inflammatory milieu of obesity and augmented by aerobic exercise. The receptor for advanced glycation endproducts (RAGE) is an inflammatory receptor directly linking metabolic dysfunction with inflammation. Circulating soluble isoforms of RAGE (sRAGE) formed either by proteolytic cleavage (cRAGE) or alternative splicing (esRAGE) act as decoys for RAGE ligands, thereby counteracting RAGE-mediated inflammation. We aimed to determine if RAGE expression or alternative splicing of RAGE is altered by obesity in muscle, and whether acute aerobic exercise (AE) modifies RAGE and sRAGE. Young (20-34 yr) participants without [n = 17; body mass index (BMI): 22.6 ± 2.6 kg/m2] and with obesity (n = 7; BMI: 32.8 ± 2.9 kg/m2) performed acute aerobic exercise (AE) at 40%, 65%, or 80% of maximal aerobic capacity (V̇o2max; mL/kg/min) on separate visits. Blood was taken before and 30 min after each AE bout. Muscle biopsy samples were taken before, 30 min, and 3 h after the 80% V̇o2max AE bout. Individuals with obesity had higher total RAGE and esRAGE mRNA and RAGE protein (P < 0.0001). In addition, RAGE and esRAGE transcripts correlated to transcripts of the NF-κB subunit P65 (P < 0.05). There was no effect of AE on total RAGE or esRAGE transcripts, or RAGE protein (P > 0.05), and AE tended to decrease circulating sRAGE in particular at lower intensities of exercise. RAGE expression is exacerbated in skeletal muscle with obesity, which may contribute to muscle inflammation via NF-κB. Future work should investigate the consequences of increased skeletal muscle RAGE on the development of obesity-related metabolic dysfunction and potential mitigating strategies.NEW & NOTEWORTHY This study is the first to investigate the effects of aerobic exercise intensity on circulating sRAGE isoforms, muscle RAGE protein, and muscle RAGE splicing. sRAGE isoforms tended to diminish with exercise, although this effect was attenuated with increasing exercise intensity. Muscle RAGE protein and gene expression were unaffected by exercise. However, individuals with obesity displayed nearly twofold higher muscle RAGE protein and gene expression, which positively correlated with expression of the P65 subunit of NF-κB.

Acute exercise modulates the inflammatory response in adipose tissue in both lean and obese mice

ObjectivesAcute physical exercise acts as a metabolic stressor, promoting activation of the immune system, and this response could be relevant in the adipose tissue remodeling process. In addition, some cytokines have important functions in lipolysis. Because chronic exercise improves obesity-related metabolic and inflammatory dysfunction, herein we investigated the effect of acute exercise on the inflammatory responses in the adipose tissues of lean and obese mice. MethodsLean mice were fed a standard chow diet, whereas obese mice were fed a high-refined carbohydrate diet for 8 wk. Both groups were subjected to 60 min of moderate-intensity exercise. ResultsIn the epididymal adipose tissue of lean mice, exercise enhanced interleukin (IL)-6 and tumor necrosis factor-α levels, which correlated positively with increased serum free fatty acid concentrations. In vivo confocal imaging of epididymal adipose tissue vessels revealed higher recruitment of neutrophils after exercise. Also, the number of leukocytes expressing CD11b+F480– was elevated 6 h after exercise. Similarly, the chemokine (C-X-C motif) ligand 1 level increased at 6 h and remained high until 24 h after exercise. Myeloperoxidase activity was increased at 6, 12, and 24 h after exercise. Surprisingly, however, no changes were observed in epididymal adipose tissue from obese mice, considering proinflammatory cytokines (IL-6 and tumor necrosis factor-α). On the other hand, IL-13, IL-4, and IL-10 levels were higher in obese mice after exercise. ConclusionsThese data suggest that acute exercise promotes an inflammatory response in the adipose tissue of lean mice that is observed as part of its role in adipose tissue remodeling. In contrast, acute exercise promotes an antiinflammatory response in adipose tissue from obese mice, likely as an important tool for restoring homeostasis.

Abstract 315: Evolution Of Mutation-driven Clonal Hematopoiesis Over 20 Years Is Associated With Low High-density Lipoprotein-cholesterol And Insulin Resistance In Patients With Obesity

Introduction: Hematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of hematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF&lt;2%) are also associated with adverse cardiovascular outcomes. Individuals with obesity have increased risk of cardiovascular disease, and it is possible that this is due to increased prevalence of hematopoietic clones. Hypothesis: We assessed the hypothesis that obesity-related metabolic dysfunction increases clonal hematopoiesis. Methods: Our aims were to determine the prevalence of clonal hematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years. Clonal hematopoiesis driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects study. Using an ultrasensitive assay, we analyzed single-timepoint samples from 1050 individuals treated by usual care and 848 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n=40) of the individuals treated by usual care. Results: Prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P=0.330), with VAF ranging from 0.01%-31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4%-27%) per year and rate of clone growth was positively associated with insulin resistance (R=0.40, P=0.025) and low HDL-cholesterol (R=-0.68, P=1.74E-05). Conclusions: Insulin resistance and low HDL-C are associated with growth of hematopoietic clones in individuals with obesity treated by usual care, supporting our hypothesis that dysfunctional metabolism affects clone growth.

Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice.

Obesity is a metabolic disorder associated with many diseases. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type E3 ubiquitin ligase involved in several diseases. Recently, we found that the level of WWP1 is increased in white adipose tissue in a mouse model of obesity and that obese Wwp1 knockout (KO) mice exhibit improved whole-body glucose metabolism. Here, to determine which insulin-sensitive tissues contribute to this phenotype, we investigated the levels of several insulin signaling markers in white adipose tissue, liver, and skeletal muscle of Wwp1 KO mice, which were fed a normal or high-fat diet and transiently treated with insulin. In obese Wwp1 KO mice, phosphorylated Akt levels were increased in the liver but not in white adipose tissue or skeletal muscle. Moreover, the weight and triglyceride content of the liver of obese Wwp1 KO mice were decreased. These results suggest that systemic deletion of WWP1 improves glucose metabolism via enhanced hepatic insulin signaling and suppressed hepatic fat accumulation. In summary, WWP1 participates in obesity-related metabolic dysfunction and pathologies related to hepatic steatosis via suppressed insulin signaling.

Ameliorative effects of zinc supplementation on cognitive function and hippocampal leptin signaling pathway in obese male and female rats

Obesity has been associated with cognitive impairments, increasing the probability of developing dementia. Recently, zinc (Zn) supplementation has attracted an increasing attention as a therapeutic agent for cognitive disorders. Here, we investigated the potential effects of low and high doses of Zn supplementation on cognitive biomarkers and leptin signaling pathway in the hippocampus of high fat diet (HFD)-fed rats. We also explored the impact of sex difference on the response to treatment. Our results revealed a significant increase in body weight, glucose, triglycerides (TG), total cholesterol (TC), total lipids and leptin levels in obese rats as compared to controls. HFD feeding also reduced brain-derived neurotrophic factor (BDNF) levels and increased acetylcholinesterase (AChE) activity in the hippocampus of both sexes. The low and high doses of Zn supplementation improved glucose, TG, leptin, BDNF levels and AChE activity in both male and female obese rats compared to untreated ones. Additionally, downregulated expression of leptin receptor (LepR) gene and increased levels of activated signal transducer and activator of transcription 3 (p-STAT3) that observed in hippocampal tissues of obese rats were successfully normalized by both doses of Zn. In this study, the male rats were more vulnerable to HFD-induced weight gain, most of the metabolic alterations and cognition deficits than females, whereas the female obese rats were more responsive to Zn treatment. In conclusion, we suggest that Zn treatment may be effective in ameliorating obesity-related metabolic dysfunction, central leptin resistance and cognitive deficits. In addition, our findings provide evidence that males and females might differ in their response to Zn treatment.

Investigation of the Possible Relation of Apelin, Kynurenine and IL-4/IL-10/IL-12/Tnf-alfa Levels with Clinical and Metabolic Parameters in Obesity

Purpose&#x0D; Obesity is a medical condition caused by excess body fat that accumulates at a level that can have a negative impact on health. Altered glucose and lipid metabolism, low-grade chronic inflammation play a role in the pathogenesis of obesity and obesity-related metabolic dysfunction. In our study, we aimed to determine the apelin, kynurenine, IL-4/IL-10/IL-12/TNF-α protein levels in obese individuals and healthy control groups, and to investigate the possible relationship between clinical parameters with the data to be obtained. &#x0D; Materials and Methods&#x0D; The levels of Apelin, Kynurenine, IL-4/IL-10/IL-12/TNF-α in serum/plasma samples were measured with enzyme-linked immunosorbent assay. Absorbance of the samples were measured on a microplate reader spectrophotometrically at a wavelength of 450 nm.&#x0D; Results&#x0D; The levels of Kinurenin, IL-4, and IL-12 in the serum were higher in control group than in obese patients (p=0.009, p=0.004, p=0.002, respectively). There was no significant difference between the control and obese patients in TNF-α, IL-10 and Apelin levels (p=0.277, p=0.711, p=0.472, respectively).&#x0D; Conclusion&#x0D; Inflammation and altered immune response are two important components of obesity. They play a major role in the formation of metabolic diseases associated with obesity. Changes in adipokine levels may lead to the development and maintenance of insulin resistance and systemic inflammation in obesity. The results demonstrate that kynurenine, IL-4, and IL-12 have a complex role in obesity and can be used as therapeutic targets.

COBL, MKX and MYOC Are Potential Regulators of Brown Adipose Tissue Development Associated with Obesity-Related Metabolic Dysfunction in Children

Obesity is already accompanied by adipose tissue (AT) dysfunction and metabolic disease in children and increases the risk of premature death. Due to its energy-dissipating function, brown AT (BAT) has been discussed as being protective against obesity and related metabolic dysfunction. To analyze the molecular processes associated with BAT development, we investigated genome-wide expression profiles in brown and white subcutaneous and perirenal AT samples of children. We identified 39 upregulated and 26 downregulated genes in uncoupling protein 1 (UCP1)-positive compared to UCP1-negative AT samples. We prioritized for genes that had not been characterized regarding a role in BAT biology before and selected cordon-bleu WH2 repeat protein (COBL), mohawk homeobox (MKX) and myocilin (MYOC) for further functional characterization. The siRNA-mediated knockdown of Cobl and Mkx during brown adipocyte differentiation in vitro resulted in decreased Ucp1 expression, while the inhibition of Myoc led to increased Ucp1 expression. Furthermore, COBL, MKX and MYOC expression in the subcutaneous AT of children is related to obesity and parameters of AT dysfunction and metabolic disease, such as adipocyte size, leptin levels and HOMA-IR. In conclusion, we identify COBL, MKX and MYOC as potential regulators of BAT development and show an association of these genes with early metabolic dysfunction in children.

Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

Avaliação da ocorrência de síndrome metabólica em cães obesos e o papel da dieta de restrição calórica como uma terapia adjuvante

Metabolic syndrome, or metabolic dysfunction related to obesity in dogs, is a set of factors that may predispose comorbidities secondary to obesity. Adjuvant therapy with an energy-restricted diet, especially with low levels of carbohydrate and fat, is essential for weight loss, in addition to controlling snacks intake. The aim of this study was to evaluate the biochemical profile of obese dogs compared to lean dogs, and also to compare these profiles before and after a 30-day treatment, thus evaluating the possibility of obesity-related metabolic dysfunction and the action of adjuvant dietary therapy in this condition. Cholesterol and its fractions (HDL, LDL and VLDL), triglycerides, systemic blood pressure and glycemia of obese and lean dogs were measured, and seven obese dogs were treated only with a low-calorie diet with low levels of fat and carbohydrates for 30 days; these patients were evaluated before and after treatment. Obese dogs showed higher levels of triglycerides than lean dogs, and dogs treated with low-calorie diet presented weight loss and better outcomes related to biochemical profile, especially triglycerides levels, after treatment.

Vitamin D Supplementation and Its Relationship with Loss of Visceral Adiposity

An inverse relationship between vitamin D (VD) nutritional status and obesity is frequent, and the distribution of body fat is an important aspect to assess the risks of obesity-related metabolic dysfunction. The purpose of the study was to evaluate the relationship between serum VD concentrations and body fat reduction after 12months of bariatric surgery, using two different vitamin D3 (VD3) supplementation protocols. A randomized controlled trial consisted of 41 patients divided into G1 (800IU/day) and G2 (1800IU/day) according to the VD3 supplementation. At baseline (T0) and follow-up (T1), 25(OH)D, waist circumference (WC), visceral adiposity index (VAI), body adiposity index (BAI), and waist/height ratio (WHtR) were evaluated. In T0, the mean of 25(OH)D was lower in G2 compared to that in G1 (22.6 vs 23.6ng/mL; p = 0.000). At T1, it had a significant increase in G2 (32.1 vs 29.9ng/mL; p = 0.000), with 60% sufficiency. A significant negative correlation was observed between VAI, BAI, and WHtR with 25(OH)D in G2 (r = - 0.746, p = 0.024; r = - 0.411, p = 0.036; r = - 0.441, p = 0.032) after surgery. Higher mean changes from baseline of visceral fat loss, represented by VAI, were observed in G2 (176.2 ± 149.0-75.5 ± 55.0, p = 0.000). Patients submitted to the 1800IU/day protocol, 12months after the surgical procedure, had a higher percentage of sufficient vitamin D levels compared to those submitted to the 800IU/day protocol. Additionally, higher dose supplementation promoted a significant improvement in VAI.

CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder

The molecular interactions that regulate chronic inflammation underlying metabolic disease remain largely unknown. Since the CD24-Siglec interaction regulates inflammatory response to danger-associated molecular patterns (DAMPs), we have generated multiple mouse strains with single or combined mutations of Cd24 or Siglec genes to explore the role of the CD24-Siglec interaction in metaflammation and metabolic disorder. Here, we report that the CD24-Siglec-E axis, but not other Siglecs, is a key suppressor of obesity-related metabolic dysfunction. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced metabolic disorders, including obesity, dyslipidemia, insulin resistance, and nonalcoholic steatohepatitis (NASH). Mechanistically, sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation to protect against metabolic syndrome. A first-in-human study of CD24Fc (NCT02650895) supports the significance of this pathway in human lipid metabolism and inflammation. These findings identify the CD24-Siglec-E axis as an innate immune checkpoint against metaflammation and metabolic disorder and suggest a promising therapeutic target for metabolic disease.

REEP6 knockout leads to defective β-adrenergic signaling in adipocytes and promotes obesity-related metabolic dysfunction.

IntroductionThe mobilization and catabolism of lipid energy is a central function of adipocytes that is under the control of the β-adrenergic signaling pathway, and defects in β-adrenergic signaling in adipocytes have been linked to obesity and obesity-related metabolic diseases. Receptor expression-enhancing proteins (REEPs) are endoplasmic reticulum (ER) proteins that play critical roles in subcellular targeting of receptor signaling complexes. Examination of gene expression profiles indicates that, among REEPs expressed in adipocytes, REEP6 expression is uniquely upregulated by sympathetic nervous system activation, suggesting involvement in regulating adrenergic signal transduction. ObjectiveThe aim of this study was to assess the contribution of REEP6 to the thermogenic activation of adipocytes and characterize the metabolic consequences of REEP6 deficiency in vivo. MethodsExpression levels of Reep6 in adipose tissue were examined by using public transcriptomic data and validated by Western blot and qPCR analyses. Adipocyte-specific regulatory roles of REEP6 were investigated in vitro in C3H10T1/2 adipocytes and in primary adipocytes obtained from REEP6 KO mice. Effects of in vivo REEP6 deficiency on energy expenditure were measured by indirect calorimetry. Mitochondrial content in adipose tissue was accessed by immunoblot, mitochondrial DNA analysis, and confocal and electron microscopy. Effects of REEP6 KO on obesity-induced metabolic dysfunction were tested in a high-fat diet-induced obesity mouse model by glucose tolerance test, Western blot, and histological analyses. ResultsREEP6 expression is highly enriched in murine adipocytes and is sharply upregulated upon adipocyte differentiation and by cold exposure. Inactivation of REEP6 in mice increased adiposity, and reduced energy expenditure and cold tolerance. REEP6 KO severely reduced protein kinase A-mediated signaling in BAT and greatly reduced mitochondrial mass. The effect of REEP6 inactivation on diminished β-adrenergic signaling was reproduced in cultured adipocytes, indicating that this effect is cell-autonomous. REEP6 KO also suppressed expression of adenylate cyclase 3 (Adcy3) in brown adipose tissue and knockdown of REEP6 in adipocytes reduced targeting of ADCY3 to the plasma membrane. Lastly, REEP6 KO exacerbated high-fat diet-induced insulin resistance and inflammation in adipose tissue. ConclusionsThis study indicates that REEP6 plays an important role in β-adrenergic signal transduction in adipocytes involving the expression and trafficking of Adcy3. Genetic inactivation of REEP6 reduces energy expenditure, increases adiposity, and the susceptibility to obesity-related metabolic dysfunction.

Artemisia scoparia and Metabolic Health: Untapped Potential of an Ancient Remedy for Modern Use.

Botanicals have a long history of medicinal use for a multitude of ailments, and many modern pharmaceuticals were originally isolated from plants or derived from phytochemicals. Among these, artemisinin, first isolated from Artemisia annua, is the foundation for standard anti-malarial therapies. Plants of the genus Artemisia are among the most common herbal remedies across Asia and Central Europe. The species Artemisia scoparia (SCOPA) is widely used in traditional folk medicine for various liver diseases and inflammatory conditions, as well as for infections, fever, pain, cancer, and diabetes. Modern in vivo and in vitro studies have now investigated SCOPA’s effects on these pathologies and its ability to mitigate hepatotoxicity, oxidative stress, obesity, diabetes, and other disease states. This review focuses on the effects of SCOPA that are particularly relevant to metabolic health. Indeed, in recent years, an ethanolic extract of SCOPA has been shown to enhance differentiation of cultured adipocytes and to share some properties of thiazolidinediones (TZDs), a class of insulin-sensitizing agonists of the adipogenic transcription factor PPARγ. In a mouse model of diet-induced obesity, SCOPA diet supplementation lowered fasting insulin and glucose levels, while inducing metabolically favorable changes in adipose tissue and liver. These observations are consistent with many lines of evidence from various tissues and cell types known to contribute to metabolic homeostasis, including immune cells, hepatocytes, and pancreatic beta-cells. Compounds belonging to several classes of phytochemicals have been implicated in these effects, and we provide an overview of these bioactives. The ongoing global epidemics of obesity and metabolic disease clearly require novel therapeutic approaches. While the mechanisms involved in SCOPA’s effects on metabolic, anti-inflammatory, and oxidative stress pathways are not fully characterized, current data support further investigation of this plant and its bioactives as potential therapeutic agents in obesity-related metabolic dysfunction and many other conditions.

Dynamic transcriptome analysis of the muscles in high-fat diet-induced obese zebrafish (Danio rerio) under 5-HT treatment

Peripheral 5-hydroxytryptamine (5-HT, also called serotonin) is reportedly a potential therapeutic target in obesity-related metabolic diseases due to its regulatory role in energy homeostasis in mammals. However, information on the detailed effect of peripheral 5-HT on the energy metabolism in fishes, especially the lipid metabolism, and the underlying mechanism remains elusive. In this study, a diet-induced obesity model was developed in the zebrafish (Danio rerio), a prototypical animal model for metabolic disorders. The zebrafish were fed a high-fat diet for 8 weeks and were simultaneously injected with PBS, 0.1 mM and 10 mM 5-HT, intraperitoneally. The body weight was significantly lower in the zebrafish injected with 0.1 mM 5-HT (P < 0.05), however, there was no change in body length (P > 0.05) at the end of the 8-week treatment. The muscle tissues from the zebrafish treated with PBS and 5-HT were collected for transcriptomic analysis and the RNA-seq revealed 1134, 3713, and 2535 genes were screened out compared to the muscular DEGs among three groups. The enrichment analysis revealed DEGs to be significantly associated with multiple metabolic pathways, including ribosome, oxidative phosphorylation, proteasome, PPAR signaling pathway, and ferroptosis. Additionally, the qRT-PCR validated 12 DEGs out of which 10 genes exhibited consistent trends. Taken together, this data provided useful information on the transcriptional characteristics of the muscle tissue in the obese zebrafish exposed to 5-HT, offering important insights into the regulatory effect of peripheral 5-HT in teleosts, as well as novel approaches for preventing and treating obesity-related metabolic dysfunction.