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Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation. [ABSTRACT FROM AUTHOR]

Lipid-associated macrophages (LAMs) occur in a broad range of diseased structures and lesions in tissues important for metabolic homeostasis. LAMs can be distinguished from other tissue-resident macrophages by their lipid-handling capacity and expression of specific marker genes (e.g., Trem2 , Gpnmb , and CD36). LAMs exhibit a functional spectrum (with respect to inflammation, lipid handling, and efferocytosis) that can vary depending on metabolic and disease state, location, and microenvironmental needs. LAM pools emerge largely from monocyte-derived precursors, but may also increase in abundance through (re-)polarization and self-renewal. Evidence for the importance of LAMs in metabolic disease justifies ventures into therapeutics that manipulate LAM abundance and phenotypes. Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of adipokines is considered a key mechanism of chronic inflammation in metabolic syndrome. Some adipokines affect food intake by crossing the blood/brain barrier. The adipokine chemerin is associated with metabolic syndrome, cardiovascular diseases and immune response. Little is known about chemerin's presence in cerebrospinal fluid (CSF) and its ability to cross the blood/CSF barrier. Methods: We quantified chemerin levels in paired serum and CSF samples of 390 patients with different neurological diagnoses via enzyme-linked immunosorbent assay (ELISA). Correlation analyses of serum and CSF chemerin levels with anthropometric, serum and CSF routine parameters were performed. Results: Overweight patients exhibited higher chemerin levels in serum and CSF. Chemerin CSF levels were higher in men. Chemerin levels in serum were associated with BMI (body mass index) and CRP (C-reactive protein). Chemerin levels in CSF were associated with age. Neurological diseases affected chemerin levels in CSF. The chemerin CSF/serum ratio was calculated as 96.3 ± 36.8 × 10−3 for the first time. Conclusions: Our data present a basis for the development of standard values for chemerin quantities in CSF. CSF chemerin levels are differentially regulated in neurological diseases and affected by BMI and sex. Chemerin is able to cross the blood/CSF barrier under physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

"Metaflammation," proposed by Hotamisligil in 2006, refers to a chronic low-grade inflammation triggered by metabolic factors such as excessive nutrition and energy, persisting at subacute levels over an extended period. Immune cells infiltrate the inflammatory site, leading to enhanced expression or activity of various inflammatory molecules and subsequent inflammatory damage. Recent research on metabolic-related fatty liver disease has revealed that modern metaflammation plays a pivotal role in the pathogenesis of NAFLD. The associated inflammatory pathways offer promising prospects for the development of targeted drugs. This article provides an updated review on the advancements in metaflammation within NAFLD. [ABSTRACT FROM AUTHOR]

Both cardiometabolic and chronic inflammatory diseases pose a significant challenge to global public health, particularly among older adults. Here, we investigated the interplay between systemic inflammatory status and the cardiometabolic index (CMI) in older men with adequate weight or obesity. In this observational cross-sectional study, older men (71.79 ± 7.35 years) were separated into groups with normal weight (NW, n = 34) and obesity (O, n = 32) to assess circulating levels of pro- and anti-inflammatory cytokines and CMI. Overall, the O group showed not only a higher inflammatory status but also increased CMI (p < 0.0001) compared with the NW group. Interestingly, only positive correlations were found between pro- and anti-inflammatory cytokines in both groups. Through multivariate regression analysis, IL-6 (β = −0.2276, p = 0.0003) and IL-10 (β = 0.2023, p = 0.0030) significantly influenced CMI in the NW group. No significant results were found in the O group. Our findings reinforce the effects of obesity in inflammaging, as well as suggesting that the influence of cytokines in CMI occurs in older men with normal weight, since the elevated pro-inflammatory profile observed in older men with obesity can interfere in this effect. [ABSTRACT FROM AUTHOR]

Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation.

Accumulating evidence illuminated that gut microbiota directly modulates the development of atherosclerosis (AS) through interactions with metaflammation. The natural bioactive isoquinoline alkaloid palmatine (PAL), which is extracted from one of the herbs (Coptis chinensis) of the anti-AS formular, is of particular interest due to its pharmacological properties. ApoE-/- mice were administered PAL or vehicle; plaque areas, and stability were assessed by histopathological and immunohistochemistry analysis, serum glycolysis and lipid levels, and inflammation levels were also evaluated. 16S rRNA sequencing and metabolomics analysis were employed to evaluate microbial composition and serum metabolites. Microbial culture experiments were designed to reveal the target microbiota and associated metabolites. Cell culture and transcriptome were performed to elucidate the function of microbial metabolites on THP-1. PAL reduced the area of plaque and necrotic core, improving inflammatory infiltration within plaques, improving glycolipid metabolism, and reducing the levels of serum inflammatory cytokines in a dose-dependent manner. PAL treatment reshaped the composition of the gut microbiota, especially, reducing the relative abundance of Desulfovibrio piger (D. piger) in a dose-dependent manner and serum level of hippuric acid (HA). D. piger was able to convert phenylalanine into 3-phenylpropionic acid (precursor of HA). Finally, we verified HA accelerated the progression of AS and increased the secretions of inflammatory cytokines in vivo and in vitro. In conclusion, PAL exhibited anti-AS effects by regulating the gut microbiota-phenylalanine metabolism axis.

Overnutrition triggers obesity and metabolic dysregulation, causing metaflammation. D-allulose, exhibits anti-obesity and hypoglycemic benefits. However, its involvement in metaflammation remains incompletely understood. In this study, high-fat diet-fed mice were supplemented with 300 mg/kg of D-allulose for 60 days. Levels of inflammation in various tissues, changes in intestinal barrier function, and gut microbiota composition, which serve as key markers of metaflammation, were analyzed. We foud that D-allulose significantly attenuated HFD-induced metaflammation, evidenced by a reduction in inflammation levels and in the activation of proinflammatory macrophages in adipose tissue. Additionally, D-allulose effectively restored impaired intestinal barrier function in HFD-fed mice by enhancing the expression of tight junction proteins, replenishing goblet cell populations, and modulating intestinal flora composition, which improved intestinal barrier integrity and contributed to the attenuation of metaflammation. Our findings highlight the potential of D-allulose in obesity and metaflammation management and provide new directions for future applications and advancements of D-allulose.

Abstract Prediabetes is an important stage in the development of diabetes. It is necessary to find a safe, effective and sustainable way to delay and reverse the progression of prediabetes. Akkermansia muciniphila (A. muciniphila) is one of the key bacteria associated with glucose metabolism. Recent studies mainly focus on the effect of A. muciniphila on obesity and insulin resistance, but there is no research on the effect of A. muciniphila on pancreatic β-cell function and its mechanism in prediabetes. In this study, we investigated the effects of A. muciniphila on β-cell function, apoptosis and differentiation, as well as its effects on the gut microbiome, intestinal barrier, metaflammation and the expression of Toll-like receptors (TLRs) in a high-fat diet (HFD)-induced prediabetic rat model. The effect of A. muciniphila was compared with dietary intervention. The results showed both A. muciniphila treatment and dietary intervention can reduce metaflammation by repairing the intestinal barrier in rats with prediabetes induced by an HFD and improve β-cell secretory function, apoptosis and differentiation through signaling pathways mediated by TLR2 and TLR4. Additionally, A. muciniphila can further elevate β-cell secretion, attenuate apoptosis and improve differentiation and the TLR signaling pathway on the basis of diet.

Prediabetes is an important stage in the development of diabetes. It is necessary to find a safe, effective and sustainable way to delay and reverse the progression of prediabetes. Akkermansia muciniphila (A. muciniphila) is one of the key bacteria associated with glucose metabolism. Recent studies mainly focus on the effect of A. muciniphila on obesity and insulin resistance, but there is no research on the effect of A. muciniphila on pancreatic β-cell function and its mechanism in prediabetes. In this study, we investigated the effects of A. muciniphila on β-cell function, apoptosis and differentiation, as well as its effects on the gut microbiome, intestinal barrier, metaflammation and the expression of Toll-like receptors (TLRs) in a high-fat diet (HFD)-induced prediabetic rat model. The effect of A. muciniphila was compared with dietary intervention. The results showed both A. muciniphila treatment and dietary intervention can reduce metaflammation by repairing the intestinal barrier in rats with prediabetes induced by an HFD and improve β-cell secretory function, apoptosis and differentiation through signaling pathways mediated by TLR2 and TLR4. Additionally, A. muciniphila can further elevate β-cell secretion, attenuate apoptosis and improve differentiation and the TLR signaling pathway on the basis of diet. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of adipokines is considered a key mechanism of chronic inflammation in metabolic syndrome. Some adipokines affect food intake by crossing the blood/brain barrier. The adipokine chemerin is associated with metabolic syndrome, cardiovascular diseases and immune response. Little is known about chemerin’s presence in cerebrospinal fluid (CSF) and its ability to cross the blood/CSF barrier. Methods: We quantified chemerin levels in paired serum and CSF samples of 390 patients with different neurological diagnoses via enzyme-linked immunosorbent assay (ELISA). Correlation analyses of serum and CSF chemerin levels with anthropometric, serum and CSF routine parameters were performed. Results: Overweight patients exhibited higher chemerin levels in serum and CSF. Chemerin CSF levels were higher in men. Chemerin levels in serum were associated with BMI (body mass index) and CRP (C-reactive protein). Chemerin levels in CSF were associated with age. Neurological diseases affected chemerin levels in CSF. The chemerin CSF/serum ratio was calculated as 96.3 ± 36.8 × 10−3 for the first time. Conclusions: Our data present a basis for the development of standard values for chemerin quantities in CSF. CSF chemerin levels are differentially regulated in neurological diseases and affected by BMI and sex. Chemerin is able to cross the blood/CSF barrier under physiological and pathophysiological conditions.

Advanced glycation end products (AGEs) exert a key pathogenic role in the development of obesity and insulin resistance. Thanks to its abundance in bioactive compounds, the microalga Arthrospira platensis (spirulina, SP) is proposed as a nutritional supplement. Here, we investigated the potential anti-glycating properties of SP enriched with zinc (Zn-SP) and the following impact on diet-induced metabolic derangements. Thirty male C57Bl6 mice were fed a standard diet (SD) or a high-fat high-sugar diet (HFHS) for 12 weeks, and a subgroup of HFHS mice received 350 mg/kg Zn-SP three times a week. A HFHS diet induced obesity and glucose intolerance and increased plasma levels of pro-inflammatory cytokines and transaminases. Zn-SP administration restored glucose homeostasis and reduced hepatic dysfunction and systemic inflammation. In the liver of HFHS mice, a robust accumulation of AGEs was detected, paralleled by increased expression of the main AGE receptor (RAGE) and depletion of glyoxalase-1, whereas Zn-SP administration efficiently prevented these alterations reducing local pro-inflammatory responses. 16S rRNA gene profiling of feces and ileum content revealed altered bacterial community structure in HFHS mice compared to both SD and HFHS + Zn-SP groups. Overall, our study demonstrates relevant anti-glycation properties of Zn-SP which contribute to preventing AGE production and/or stimulate AGE detoxification, leading to the improvement of diet-related dysbiosis and metabolic derangements. [ABSTRACT FROM AUTHOR]

The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss. In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays. We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity. Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss. [ABSTRACT FROM AUTHOR]

Emerging lines of evidence have shown that the production of the covalently closed single-stranded circular RNAs is not splicing errors, but rather a regulated process with distinct biogenesis and turnover. Circular RNAs are expressed in a cell type- and tissue-specific manner and often localize to specific subcellular regions or organelles for functions. The dysregulation of circular RNAs from birth to death is linked to the pathogenesis and progression of diverse diseases. This review outlines how aberrant circular RNA biogenesis, subcellular location, and degradation are linked to disease progression, focusing on metaflammation and cancers. We also discuss potential therapeutic strategies and obstacles in targeting such disease-related circular RNAs.

Cardiometabolic diseases (CMDs) are characterized by a series of metabolic disorders and chronic low-grade inflammation. CMDs contribute to a high burden of mortality and morbidity worldwide. Host-microbial metabolic regulation that triggers metaflammation is an emerging field of study that promotes a new perspective for perceiving cardiovascular risks. The term metaflammation denotes the entire cascade of immune responses activated by a new class of metabolites known as “danger-associated metabolites” (DAMs). It is being proposed by the present review for the first time. We summarize current studies covering bench to bedside aspects of DAMs to better understand CMDs in the context of DAMs. We have focused on the involvement of DAMs in the pathophysiological development of CMDs, including the disruption of immune homeostasis and chronic inflammation–triggered damage leading to CMD-related adverse events, as well as emerging therapeutic approaches for targeting DAM metabolism in CMDs.

Equine metabolic syndrome (EMS) is a steadily growing endocrine disorder representing a real challenge in veterinary practice. As a multifactorial condition, EMS is characterized by three main metabolic abnormalities including insulin resistance, increased adiposity or obesity and hoof laminitis. Adipose tissue dysfunction is recognized as a core pathophysiological determinant of EMS, as it strongly participates to lipotoxicity and systemic metaflammation, both of which have been closely linked to the development of generalized insulin resistance. Besides, sex hormone binding globulin (SHBG) is an important sex steroids transporters that has been recently proposed as an important metabolic mediator. Therefore, the aim of this study was to verify whether SHBG treatment may ameliorate subcutaneous adipose tissue metabolic failure under EMS condition in terms of lipidome homeostasis, lipid metabolism programs, insulin signalling and local inflammation. Subcutaneous adipose tissue (SAT) biopsies were collected post-mortem from healthy (n = 3) and EMS (n = 3) slaughtered horses. SHBG protein has been applied to SAT samples from EMS horses for 24 h at a final concentration of 50 nM, while control groups (healthy and untreated EMS) were cultured in the presence of SHBG-vehicle only. Tissues from all groups were afterwards secured for downstream analysis of gene expression using RT-qPCR, protein levels by Western blot and ELISA assay and lipidomics through GC-MS technique. Obtained results showcased that SHBG intervention efficiently normalized the altered fatty acids (FAs) profiles by lowering the accumulation of saturated and trans FAs, as well as the pro-inflammatory arachidonic and linoleic acids. Moreover, SHBG showed promising value for the regulation of adipocyte lipolysis and engorgement by lowering the levels of perilipin-1. SHBG exerted moderated effect toward SCD1 and FASN enzymes expression, but increased the LPL abundance. Interestingly, SHBG exhibited a negative regulatory effect on pro-adipogenic stimulators and induced higher expression of KLF3, IRF3 and β-catenin, known as strong adipogenesis repressors. Finally, SHBG protein showed remarkable ability in restoring the insulin signal transduction, IR/IRS/Pi3K/AKT phosphorylation events and GLUT4 transporter abundance, and further attenuate pro-inflammatory response by lowering IL-6 tissue levels and targeting the PDIA3/ERK axis. Overall, the obtained data clearly demonstrate the benefice of SHBG treatment in the regulation of adipose tissue metabolism in the course of EMS and provide new insights for the development of molecular therapies with potential translational application to human metabolic disorders.

Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.

Western dietary habits (WD) have been shown to promote chronic inflammation, which favors the development of many of today's non-communicable diseases. Recently, ketogenic diets (KD) have emerged as an immune-regulating countermeasure for WD-induced metaflammation. To date, beneficial effects of KD have been solely attributed to the production and metabolism of ketone bodies. Given the drastic change in nutrient composition during KD, it is reasonable to assume that there are widespread changes in the human metabolome also contributing to the impact of KD on human immunity. The current study was conducted to gain insight into the changes of the human metabolic fingerprint associated with KD. This could allow to identify metabolites that may contribute to the overall positive effects on human immunity, but also help to recognize potential health risks of KD. We conducted a prospective nutritional intervention study enrolling 40 healthy volunteers to perform a three-week ad-libitum KD. Prior to the start and at the end of the nutritional intervention serum metabolites were quantified, untargeted mass spectrometric metabolome analyses and urine analyses of the tryptophan pathway were performed. KD led to a marked reduction of insulin (−21.45% ± 6.44%, p = 0.0038) and c-peptide levels (−19.29% ± 5.45%, p = 0.0002) without compromising fasting blood glucose. Serum triglyceride concentration decreased accordingly (−13.67% ± 5.77%, p = 0.0247), whereas cholesterol parameters remained unchanged. LC-MS/MS-based untargeted metabolomic analyses revealed a profound shift of the human metabolism towards mitochondrial fatty acid oxidation, comprising highly elevated levels of free fatty acids and acylcarnitines. The serum amino acid (AA) composition was rearranged with lower abundance of glucogenic AA and an increase of BCAA. Furthermore, an increase of anti-inflammatory fatty acids eicosatetraenoic acid (p < 0.0001) and docosahexaenoic acid (p = 0.0002) was detected. Urine analyses confirmed higher utilization of carnitines, indicated by lower carnitine excretion (−62.61% ± 18.11%, p = 0.0047) and revealed changes to the tryptophan pathway depicting reduced quinolinic acid (−13.46% ± 6.12%, p = 0.0478) and elevated kynurenic acid concentrations (+10.70% ± 4.25%, p = 0.0269). A KD fundamentally changes the human metabolome even after a short period of only three weeks. Besides a rapid metabolic switch to ketone body production and utilization, improved insulin and triglyceride levels and an increase in metabolites that mediate anti-inflammation and mitochondrial protection occurred. Importantly, no metabolic risk factors were identified. Thus, a ketogenic diet could be considered as a safe preventive and therapeutic immunometabolic tool in modern medicine. German Clinical Trials Register; DRKS-ID: DRKS00027992 (www.drks.de). [ABSTRACT FROM AUTHOR]

Abstract As a result of the obesity epidemic, more people are concerned about losing weight; however, weight regain is common, leading to repeated weight loss and weight cycling. The health benefits of early weight loss are nullified by weight regain after weight cycling, which has much more severe metabolic consequences. Weight cycling alters body composition, resulting in faster fat recovery and slower muscle reconstruction. This evident fat accumulation, muscle loss, and ectopic fat deposition destroy the intestinal barrier, increase the permeability of the small intestinal epithelium, and cause the lipotoxicity of lipid metabolites and toxins to leak into extraintestinal tissues and circulation. It causes oxidative stress and hypoxia in local tissues and immune cell infiltration in various tissues, all contributing to the adaptation to this metabolic change. Immune cells transmit inflammatory responses in adipose and skeletal muscle tissue by secreting cytokines and adipokines, which mediate immune cell pathways and cause metaflammation and inefficient metabolic degradation. In this review, we focus on the regulatory function of the immunological microenvironment in the final metabolic outcome, with a particular emphasis on the cellular and molecular processes of local and systemic metaflammation induced by weight cycling-induced changes in body composition. Metaflammation in adipose and muscle tissues that is difficult to relieve may cause weight cycling. As this chronic low-grade inflammation spreads throughout the body, metabolic complications associated with weight cycling are triggered. Inhibiting the onset and progression of metabolic inflammation and enhancing the immune microenvironment of adipose and muscle tissues may be the first step in addressing weight cycling.

Importance: Endogenous Cushing's syndrome (CS) leads to profound immunosuppression. Successful surgery induces biochemical remission and reversal of immunosuppression, which is characterized by clinical signs of glucocorticoid withdrawal and associated with increased susceptibility to infections and thromboembolic complications. Objective: We hypothesized that the glucocorticoid withdrawal phase is characterized by low-grade inflammation that may be related to patientrelevant outcomes. Setting: In this retrospective observational study, we analyzed longitudinal data from 80 patients with CS prospectively enrolled in the German Cushing's registry between 2012 and 2021. All enrolled patients underwent successful surgery. In a second step, a case-control study was performed in 25 of the patients with age-, gender-, and body mass index-matched control patients in whom hypercortisolism was excluded. Analyses included the inflammatory markers C-reactive protein and interleukin-6, as well as body composition, muscle function testing, and quality-of-life questionnaires. The patients were studied during active CS and in the postoperative remission phase 1, 3, 6, 12, and 24 months after surgery. Results: Compared with the preoperative phase and matched controls, patients with CS had increased systemic inflammatory markers in the early remission phase. One month following surgery, median (interquartile range) C-reactive protein was 0.48 mg dL-1 (0.14-0.90) vs 0.10 mg dL-1 (0.06-0.39) during active CS (P = .001). Similarly, interleukin-6 1 month after surgery was 7.2 pg mL-1 (3.3-11.7) vs 1.7 pg mL-1 (1.5-2.5) during active CS (P = .001). Obesity and hemoglobin A1c (HbA1c) were associated with increased inflammation levels. This proinflammatory state lasted until 1 year following surgery. Moreover, inflammatory markers during early remission showed an inverse correlation with long-term muscle function. Conclusions: The glucocorticoid withdrawal phase is associated with a low-grade inflammatory state, which is particularly pronounced in obese and hyperglycemic patients and related to lower muscle function. [ABSTRACT FROM AUTHOR]

Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases. [ABSTRACT FROM AUTHOR]

As a result of the obesity epidemic, more people are concerned about losing weight; however, weight regain is common, leading to repeated weight loss and weight cycling. The health benefits of early weight loss are nullified by weight regain after weight cycling, which has much more severe metabolic consequences. Weight cycling alters body composition, resulting in faster fat recovery and slower muscle reconstruction. This evident fat accumulation, muscle loss, and ectopic fat deposition destroy the intestinal barrier, increase the permeability of the small intestinal epithelium, and cause the lipotoxicity of lipid metabolites and toxins to leak into extraintestinal tissues and circulation. It causes oxidative stress and hypoxia in local tissues and immune cell infiltration in various tissues, all contributing to the adaptation to this metabolic change. Immune cells transmit inflammatory responses in adipose and skeletal muscle tissue by secreting cytokines and adipokines, which mediate immune cell pathways and cause metaflammation and inefficient metabolic degradation. In this review, we focus on the regulatory function of the immunological microenvironment in the final metabolic outcome, with a particular emphasis on the cellular and molecular processes of local and systemic metaflammation induced by weight cycling-induced changes in body composition. Metaflammation in adipose and muscle tissues that is difficult to relieve may cause weight cycling. As this chronic low-grade inflammation spreads throughout the body, metabolic complications associated with weight cycling are triggered. Inhibiting the onset and progression of metabolic inflammation and enhancing the immune microenvironment of adipose and muscle tissues may be the first step in addressing weight cycling. [ABSTRACT FROM AUTHOR]

As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKβ and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes. [ABSTRACT FROM AUTHOR]

Background and Aims: Obesity is associated with chronic inflammation and oxidative stress. Weight loss after bariatric surgery improves the inflammatory state and risk of cardiovascular disease. Improvement in metabolic dysfunction might be associated with changes in the activity of sirtuin 1 (SIRT1) and we aimed to investigate the effect of bariatric surgery on its circulating levels.Methods and Results: This is a sub-study of a prospective cohort study, including 110 subjects with morbid obesity. The surgical procedure was either laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Blood was sampled at inclusion and six and 12 months after surgery. SIRT1 was measured in EDTA plasma with an enzyme-linked immunosorbent assay. The mean age in the population was 43 years, 80% were women and mean body mass index (BMI) was 38.8 kg/m2. RYGB and SG were performed in 89 and 21 subjects, respectively. SIRT1 concentration was significantly reduced from baseline to six and 12 months after surgery, with mean values (SD) 156.8 (82.6), 119.5 (65.6) and 94.9 (45.6) ng/mL, respectively, (p ≤ 0.002, all), accompanied by significant reductions in C-reactive protein (CRP), BMI and triglycerides from inclusion (p < 0.001, all). Type of surgery did not differently modify SIRT1 levels (p = 0.09). CRP and triglycerides were both positively predictive of SIRT1 levels (p ≤ 0.001, both).Conclusion: SIRT1 concentration was significantly lower six and 12 months after bariatric surgery. CRP and triglycerides independently predicted SIRT1 levels, suggesting that reduction in SIRT1 levels might not intrinsically be related to weight reduction, but to improvement in metaflammation. [ABSTRACT FROM AUTHOR]

Accumulating evidence illuminated that gut microbiota directly modulates the development of atherosclerosis (AS) through interactions with metaflammation. The natural bioactive isoquinoline alkaloid palmatine (PAL), which is extracted from one of the herbs (Coptis chinensis) of the anti-AS formular, is of particular interest due to its pharmacological properties. ApoE-/- mice were administered PAL or vehicle; plaque areas, and stability were assessed by histopathological and immunohistochemistry analysis, serum glycolysis and lipid levels, and inflammation levels were also evaluated. 16S rRNA sequencing and metabolomics analysis were employed to evaluate microbial composition and serum metabolites. Microbial culture experiments were designed to reveal the target microbiota and associated metabolites. Cell culture and transcriptome were performed to elucidate the function of microbial metabolites on THP-1. PAL reduced the area of plaque and necrotic core, improving inflammatory infiltration within plaques, improving glycolipid metabolism, and reducing the levels of serum inflammatory cytokines in a dose-dependent manner. PAL treatment reshaped the composition of the gut microbiota, especially, reducing the relative abundance of Desulfovibrio piger (D. piger) in a dose-dependent manner and serum level of hippuric acid (HA). D. piger was able to convert phenylalanine into 3-phenylpropionic acid (precursor of HA). Finally, we verified HA accelerated the progression of AS and increased the secretions of inflammatory cytokines in vivo and in vitro. In conclusion, PAL exhibited anti-AS effects by regulating the gut microbiota-phenylalanine metabolism axis. [Display omitted] • Palmatine (PAL) protects against atherosclerosis (AS) mainly by reshaping gut microbiota and phenylalanine metabolism. • PAL decreases the relative abundance of Desulfovibrio piger (D. piger) in the gut and serum level of hippuric acid (HA). • D. piger catabolizes phenylalanine into the precursor of HA. • HA is positive associated to AS and exhibits proinflammatory effects in vitro. [ABSTRACT FROM AUTHOR]

[Display omitted] • D-allulose significantly reduced metaflammation induced by HFD. • D-allulose alleviated the activation of metabolically activated macrophages (MMe) in adipose tissue. • D-allulose restored the intestinal barrier function and reduce circulating LPS levels. • D-allulose improved the HFD-induced changes in the composition of intestinal flora. Overnutrition triggers obesity and metabolic dysregulation, causing metaflammation. D-allulose, exhibits anti-obesity and hypoglycemic benefits. However, its involvement in metaflammation remains incompletely understood. In this study, high-fat diet-fed mice were supplemented with 300 mg/kg of D-allulose for 60 days. Levels of inflammation in various tissues, changes in intestinal barrier function, and gut microbiota composition, which serve as key markers of metaflammation, were analyzed. We foud that D-allulose significantly attenuated HFD-induced metaflammation, evidenced by a reduction in inflammation levels and in the activation of proinflammatory macrophages in adipose tissue. Additionally, D-allulose effectively restored impaired intestinal barrier function in HFD-fed mice by enhancing the expression of tight junction proteins, replenishing goblet cell populations, and modulating intestinal flora composition, which improved intestinal barrier integrity and contributed to the attenuation of metaflammation. Our findings highlight the potential of D-allulose in obesity and metaflammation management and provide new directions for future applications and advancements of D-allulose. [ABSTRACT FROM AUTHOR]

Background & Aims: Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that confers a broad range of functional effects in metabolic diseases. Lean nonalcoholic fatty liver disease (NAFLD) is characterized by a decrease in subcutaneous fat and ectopic fat deposition in the liver. SCAP may mediate the development of lean NAFLD, but the mechanism of action remains unclear. Methods: C57BL/6J wild-type and macrophage SCAP-specific knockout mice (SCAPΔMϕ) were subjected to Paigen diet (PD) feeding induced lean NAFLD. Inflammation and lipid metabolism of adipose and liver were evaluated. The STING–NF-κB signaling pathway was examined in vivo and in vitro to explore the underlying mechanism of macrophage SCAP on metaflammation. Results: The data showed heterogeneity of lipid metabolic processes in liver and epididymal white adipose tissue due to inflammation mediated by macrophage infiltration. Meanwhile, we found that the macrophage SCAP was abnormally increased in the adipose and liver tissues of PD-fed mice. Intriguingly, the SCAPΔMϕ mice attenuated PD-induced metaflammation and ectopic lipid deposition by reducing hepatic stimulator of interferon gene (STING)–nuclear factor kappa B (NF-κB) pathway activation. In-depth molecular analysis revealed that SCAP specifically recruits the STING and tank-binding kinase 1 onto the Golgi to activate the NF-κB in macrophages, thereby promoting the release of inflammatory factors. This process ultimately led to an increased lipolysis in adipocytes and lipid uptake and synthesis in hepatocytes. Conclusions: Our findings suggest that SCAP acts as a novel regulator of the macrophage inflammatory response and the pathogenesis of lean NAFLD by activating the STING–NF-κB signaling pathway. Inhibition of macrophage SCAP may represent a new therapeutic strategy for the treatment of lean NAFLD.

Overweight and obesity are associated with chronic low-grade inflammation and represent risk factors for various diseases, including COVID-19. However, most published studies on COVID-19 defined obesity by the body mass index (BMI), which does not encounter adipose tissue distribution, thus neglecting immunometabolic high-risk patterns. Therefore, we comprehensively analyzed baseline anthropometry (BMI, waist-to-height-ratio (WtHR), visceral (VAT), epicardial (EAT), subcutaneous (SAT) adipose tissue masses and liver fat, inflammation markers (CRP, ferritin, interleukin-6), and immunonutritional scores (CRP-to-albumin ratio (CAR), modified Glasgow prognostic score, neutrophile-to-lymphocyte ratio, prognostic nutritional index)) in 58 consecutive COVID-19 patients of the early pandemic phase with regard to the necessity of invasive mechanical ventilation (IMV). Here, metabolically high-risk adipose tissues represented by increased VAT, liver fat, and WtHR strongly correlated with higher levels of inflammation, pathologic immunonutritional scores, and the need for IMV. In contrast, the prognostic value of BMI was inferior and absent with regard to SAT. Multivariable logistic regression analysis identified an optimized IMV risk prediction model employing liver fat, WtHR, and CAR. In summary, we suggest an immunometabolically risk-adjusted model to predict COVID-19-induced respiratory failure better than BMI-based stratification, which warrants prospective validation. [ABSTRACT FROM AUTHOR]

Meta-inflammation is a chronic, low-grade state of inflammation secondary to cardiometabolic disorders related to overweight (OW), obesity (OB), consumption of poor nutritional and hypercaloric diets with excessive amounts of lipids and sugars. It can lead to severe metabolic and cardiovascular diseases. Several studies have reported that plant-based diets (PBDs) can be a useful non-pharmacological therapeutic tool for the prevention and treatment of meta-inflammation, since it has been reported that patients following PBDs have lower serum levels of proinflammatory markers, a reduction in weight, and an overall healthier lipid profile. In this review, we describe the pathophysiology of meta-inflammation, the growing worldwide trend toward adoption of PBDs, and how PBDs act to reduce meta-inflammation. [ABSTRACT FROM AUTHOR]

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Type 2 diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, chronic inflammation, impaired insulin secretion, and/or peripheral insulin resistance. Current α-glucosidase inhibitors approved for clinical use exhibit limited efficacy compared to other glucose-lowering agents. In this study, a series of mono- and bis-benzylidene derivatives were synthesized via aldol condensation of 3-oxo-dammarane triterpenoids with terephthalic aldehyde. The target mono- and bis-benzylidene derivatives, based on the dammarane triterpenoids hollongdione 1, (20S)-23,24-epoxy-25,26,27-trinordammar-3,24-dione 2, and 24(R,S)-20(S)-epoxy-25-hydroxy-dammar-3-one 3, were successfully synthesized. Several of these inhibitors demonstrated significantly greater efficacy than the reference drug acarbose. Notably, compound 4 inhibited S. cerevisiae α-glucosidase with an IC 50 of 2.67 μM. Furthermore, the target compounds effectively inhibited NLRP3 inflammasome activation, reducing IL-1β production in LPS+ATP-stimulated murine peritoneal macrophages without detectable cytotoxicity. Compound 8, which exhibited dual activity, was further characterized as an inhibitor of NLRP3 activation in peripheral blood mononuclear cells, leading to the prevention of pyroptosis and IL-1β release. Additionally, compound 8 was shown to promote neuronal survival in LPS+ATP-treated rat hippocampal slices, highlighting its potential as a promising antidiabetic agent that targets both postprandial hyperglycemia and metaflammation., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Type 2 diabetes mellitus (T2DM) is a classic metaflammatory disease, and the inflammatory states of the pancreatic islet and insulin target organs have been well confirmed. However, abundant evidence demonstrates that there are countless connections between these organs in the presence of a low degree of inflammation. In this review, we focus on cell-cell crosstalk among local cells in the islet and organ-organ crosstalk among insulin-related organs. In contrast to that in acute inflammation, macrophages are the dominant immune cells causing inflammation in the islets and insulin target organs in T2DM. In the inflammatory microenvironment (IME) of the islet, cell-cell crosstalk involving local macrophage polarization and proinflammatory cytokine production impair insulin secretion by β-cells. Furthermore, organ-organ crosstalk, including the gut-brain-pancreas axis and interactions among insulin-related organs during inflammation, reduces insulin sensitivity and induces endocrine dysfunction. Therefore, this crosstalk ultimately results in a cascade leading to β-cell dysfunction. These findings could have broad implications for therapies aimed at treating T2DM. [Display omitted] • T2DM is a systemic metaflammatory disease, including multiple interactions between the immune response and metabolism. • Under normal conditions, islet-resident macrophages make an essential contribution to maintain β-cell mass and proliferation. • Crosstalk between M1-like macrophages and β-cells in the inflammatory condition leads to β-cell apoptosis and dysfunction. • Gut absorbs excess nutrition to cause hypothalamus inflammation and energy imbalance. • Crosstalk among inflammatory insulin-related organs induces insulin resistance and β-cell dysfunction. [ABSTRACT FROM AUTHOR]

BET proteins, which recognize and bind to acetylated histones, play a key role in transcriptional regulation. The development of chemical BET inhibitors in 2010 greatly facilitated the study of these proteins. BETs play crucial roles in cancer, inflammation, heart failure, and fibrosis. In particular, BETs may be involved in regulating metabolic processes, such as adipogenesis and metaflammation, which are under tight transcriptional regulation. In addition, acetyl-CoA links energy metabolism with epigenetic modification through lysine acetylation, which creates docking sites for BET. Given this, it is possible that the ambient energy status may dictate metabolic gene transcription via a BET-dependent mechanism. Indeed, recent studies have reported that various BET proteins are involved in both metabolic signaling regulation and disease. Here, we discuss some of the most recent information on BET proteins and their regulation of the metabolism in both cellular and animal models. Further, we summarize data from some randomized clinical trials evaluating BET inhibitors for the treatment of metabolic diseases. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MS) is a group of clinical abnormalities characterized by central or abdominal obesity, hypertension, hyperuricemia, and metabolic disorders of glucose or lipid. Currently, the prevalence of MS is estimated about 25% in general population and is progressively increasing, which has become a challenging public health burden. Long-term metabolic disorders can activate the immune system and trigger a low-grade chronic inflammation named "metaflammation." As an important organ involved in metabolism, the kidney is inevitably attacked by immunity disequilibrium and "metaflammation." Recently, accumulating studies have suggested that the complement system, the most important and fundamental component of innate immune responses, is actively involved in the development of metabolic kidney diseases. In this review, we updated and summarized the different pathways through which the complement system is activated in a series of metabolic disturbances and the mechanisms on how complement mediate immune cell activation and infiltration, renal parenchymal cell damage, and the deterioration of renal function provide potential new biomarkers and therapeutic options for metabolic kidney diseases. [ABSTRACT FROM AUTHOR]

Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice.

Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation. [ABSTRACT FROM AUTHOR]

Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the "Suppressor Of Cytokine Signaling 1 and 3" (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the "typical western" conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation. [ABSTRACT FROM AUTHOR]

Objective: Obesity was once considered a risk factor for knee osteoarthritis (OA) primarily for biomechanical reasons. Here we provide an additional perspective by discussing how obesity also increases OA risk by altering metabolism and inflammation.Design: This narrative review is presented in four sections: 1) metabolic syndrome and OA, 2) metabolic biomarkers of OA, 3) evidence for dysregulated chondrocyte metabolism in OA, and 4) metabolic inflammation: joint tissue mediators and mechanisms.Results: Metabolic syndrome and its components are strongly associated with OA. However, evidence for a causal relationship is context dependent, varying by joint, gender, diagnostic criteria, and demographics, with additional environmental and genetic interactions yet to be fully defined. Importantly, some aspects of the etiology of obesity-induced OA appear to be distinct between men and women, especially regarding the role of adipose tissue. Metabolomic analyses of serum and synovial fluid have identified potential diagnostic biomarkers of knee OA and prognostic biomarkers of disease progression. Connecting these biomarkers to cellular pathophysiology will require future in vivo studies of joint tissue metabolism. Such studies will help reveal when a metabolic process or a metabolite itself is a causal factor in disease progression. Current evidence points towards impaired chondrocyte metabolic homeostasis and metabolic-immune dysregulation as likely factors connecting obesity to the increased risk of OA.Conclusions: A deeper understanding of how obesity alters metabolic and inflammatory pathways in synovial joint tissues is expected to provide new therapeutic targets and an improved definition of "metabolic" and "obesity" OA phenotypes. [ABSTRACT FROM AUTHOR]

Summary: Obesity is a chronic condition whose management is a critical challenge for physicians. The scientific community has increased its focus on the molecular mechanisms involved in obesity etiopathogenesis to better manage patients with obesity and its associated complications. The tight connection between adipose tissue and the immune system has been demonstrated to play a crucial role in inflammation, and melatonin is important for circadian rhythm regulation and metabolic homeostasis, in which it orchestrates several molecular mechanisms involved in obesity and associated inflammation. Melatonin also regulates innate and adaptive immunity; its antioxidant properties are linked to reduced predisposition to infection and weight gain in patients with obesity through the modulation of the immune response, which has a significant beneficial effect on inflammation and, consequently, on the metabolic state. Low melatonin levels have been linked to obesity, and melatonin supplementation can reduce body weight, improve metabolic profile, and ameliorate immune responses and pro‐inflammatory stimuli. The role of melatonin in obesity is mainly related to improved oxidative stress signaling, modulation of adipokine secretion, and a switching from white‐to‐brown adipose tissue phenotype and activity. Moreover, the role of melatonin in obesity modulation by controlling circadian rhythm has recently emerged as a pivotal mechanism for lipid and glucose metabolism dysfunction in adipose, muscle, and liver tissues. Melatonin may also regulate the immune system by acting directly on thymus morphology and activity as well as by modulating oxidative stress and inflammatory states during infections. The tight association between melatonin and immune response regulation is coordinated by Toll‐like receptors, which are rhythmically expressed during the day. Their expression may be strongly modulated by melatonin as their signaling is highly inhibited by melatonin. The current review summarizes studies of melatonin‐induced mechanisms involved in infection regulation, particularly the modulation of obesity‐associated inflammation and systemic complications. [ABSTRACT FROM AUTHOR]

The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunction, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways. [ABSTRACT FROM AUTHOR]

Worldwide stroke is increasing in parallel with modernization, changes in lifestyle, and the growing elderly population. Our review is focused on the link between diet, as part of ‘modern lifestyle’, and health in the context of genetic predisposition of individuals to ‘unhealthy’ metabolic pathway activity. It is concluded that lifestyle including high sugar diets, alcohol and tobacco addiction or high fat diets as well as ageing, brain injury, oxidative stress and neuroinflammation, negatively influence the onset, severity and duration of neurodegenerative diseases. Fortunately, there are several healthy dietary components such as polyunsaturated fatty acids and the anti-oxidants curcumin, resveratrol, blueberry polyphenols, sulphoraphane, salvionic acid as well as caloric restriction and physical activity, which may counteract ageing and associated neurodegenerative diseases via increased autophagy or increased neurogenesis in the adult brain.

Introduction: Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined., Objectives: We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet., Methods: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue., Results: Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation., Conclusion: Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity., 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. Production and hosting by Elsevier B.V.)

Inflammation is a pathological hallmark associated with bacterial and viral infections, autoimmune diseases, genetic disorders, obesity and diabetes, as well as environmental stresses including physical and chemical trauma. Among numerous proteins regulating proinflammatory signaling, very few such as Protein kinase R (PKR), have been shown to play an all‐pervading role in inflammation induced by varied stimuli. PKR was initially characterized as an interferon‐inducible gene activated by viral double‐stranded RNA with a role in protein translation inhibition. However, it has become increasingly clear that PKR is involved in multiple pathways that promote inflammation in response to stress activation, both dependent on and independent of its cellular protein activator of PKR (PACT). In this review, we discuss the signaling pathways that contribute to the initiation of inflammation, including Toll‐like receptor, interferon, and RIG‐I‐like receptor signaling, as well as inflammasome activation. We go on to discuss the specific roles that PKR and PACT play in such proinflammatory signaling, as well as in metabolic syndrome‐ and environmental stress‐induced inflammation. [ABSTRACT FROM AUTHOR]