Targeting the immunoproteasome in hypothalamic neurons as a novel therapeutic strategy for high-fat diet-induced obesity and metabolic dysregulation.

OBJECTIVE: Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases. METHODS: The levels of the immunoproteasome ß5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome ß5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of ß5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay. RESULTS: Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the ß5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA. CONCLUSIONS: Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.

Celiac Disease, Gluten-Free Diet and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Celiac disease (CD) is a chronic autoimmune disorder triggered by the ingestion of gluten-containing food by genetically predisposed individuals. Hence, treatment of CD consists of permanent avoidance of wheat, rye, barley, and other gluten-containing foods. Lifelong adherence to a gluten-free diet (GFD) improves the symptoms of CD, but recent evidence suggests it is also associated with a higher risk for hepatic steatosis and the coexistence or emergence of other cardiometabolic risk factors. Moreover, a higher risk for liver steatosis is also reported by some authors as a potential extraintestinal complication of the CD itself. Recent nomenclature changes designate the association between hepatic steatosis and at least one of five cardiometabolic risk factors as metabolic dysfunction-associated steatotic liver disease (MASLD). An extended network of potentially causative factors underlying the association between MAFLD and CD, before and after dietary therapy is implemented, was recently described. The individualized treatment of these patients is less supported by evidence, with most of the current recommendations relying on empiric clinical judgment. This review focuses on the causative associations between CD and hepatic injury, either as an extraintestinal manifestation of CD or a side effect of GFD, also referring to potential therapeutic strategies for these individuals.

Obesity and Obesity-Related Disorders-Editorial.

Obesity and obesity-related complications, including various metabolic diseases and cancers, are significant health problems in developed and developing countries [...].

Childhood obesity is associated with a high degree of metabolic disturbance in children from Brazilian semi-arid region.

Projected to impact 310 million children by the next decade, childhood obesity is linked to serious health issues like metabolic disturbance and cardiovascular diseases. This study introduces a novel approach for the integrated assessment of inflammatory, glycemic and lipid disorders in obese children in resources-limited settings and also identifies key factors contributing to these changes. Conducting a cross-sectional analysis of 231 children aged 5-12 years from public schools in Brazil's semi-arid region, the research involved collecting medical history, anthropometric measurements, and blood samples to analyze glycemic and lipid profiles, along with C-reactive protein levels. We used an adapted the Molecular Degree of Perturbation model to analyze deviations in metabolic markers from a healthy control group. Statistical analyses included Mann-Whitney and Fisher exact tests, backward logistic regression, and hierarchical cluster analysis. The study identified a direct and independent association between elevated Metabolic Disturbance Degree and both overweight and obesity in children, with significant differences in CRP, Triglycerides, and HDL levels noted between obese and healthy-weight groups. The findings highlight the critical need for early detection and comprehensive understanding of obesity-related changes to mitigate the severe health risks associated with childhood obesity.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

BACKGROUND: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease. METHODS: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. RESULTS: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3 × 10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. CONCLUSIONS: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options.

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.

Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets.

Cardiometabolic diseases (CMDs) encompass a range of prevalent, often preventable, non-communicable illnesses, including myocardial infarction, stroke, cardiac insufficiency, arterial hypertension, obesity, type 2 diabetes mellitus, insulin resistance, chronic renal dysfunction, non-alcoholic fatty liver disease, and rare metabolic disorders [...].

[Guidelines for the prevention and treatment of metabolic dysfunction-associated (non-alcoholic) fatty liver disease (Version 2024)].

The Chinese Society of Hepatology of the Chinese Medical Association invited relevant experts to revise and update the Guideline of Prevention and Treatment of Nonalcoholic Fatty Liver Disease (2018Version) and renamed it as (Version 2024) Guideline for the Prevention and Treatment of Metabolic Dysfunction-associated (non-alcoholic) Fatty Liver Disease. Herein, the guiding recommendations on clinical issues such as screening and monitoring, diagnosis and evaluation, treatment and follow-up of metabolic dysfunction-associated fatty liver disease are put forward.

Social and environmental stressors of cardiometabolic health.

Exposures to social and environmental stressors arise individual behavioural response and thus indirectly affect cardiometabolic health. The aim of this study was to investigate several social and environmental stressors and the paths of their influence on cardiometabolic health. The data of 2154 participants (aged 25-64 years) from the cross-sectional population-based study were analysed. The composite score of metabolic disorders (MS score) was calculated based on 5 biomarkers: waist circumference, blood pressure, fasting blood glucose, HDL-cholesterol, triglycerides. The effects of social stressors (education level, income), environmental stressors (NO2, noise) and behavioural factors (unhealthy diet, smoking, alcohol consumption, sedentary behaviours) on MS score were assessed using a structural model. We observed a direct effect of education on MS score, as well as an indirect effect mediated via an unhealthy diet, smoking, and sedentary behaviours. We also observed a significant indirect effect of income via sedentary behaviours. The only environmental stressor predicting MS was noise, which also mediated the effect of education. In summary, the effect of social stressors on the development of cardiometabolic risk had a higher magnitude than the effect of the assessed environmental factors. Social stressors lead to an individual's unhealthy behaviour and might predispose individuals to higher levels of environmental stressors exposures.

Phytonanotherapy for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, is a steatotic liver disease associated with metabolic syndrome (MetS), especially obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. MASLD in 43-44% of patients can progress to metabolic dysfunction-associated steatohepatitis (MASH), and 7-30% of these cases will progress to liver scarring (cirrhosis). To date, the mechanism of MASLD and its progression is not completely understood and there were no therapeutic strategies specifically tailored for MASLD/MASH until March 2024. The conventional antiobesity and antidiabetic pharmacological approaches used to reduce the progression of MASLD demonstrated favorable peripheral outcomes but insignificant effects on liver histology. Alternatively, phyto-synthesized metal-based nanoparticles (MNPs) are now being explored in the treatment of various liver diseases due to their unique bioactivities and reduced bystander effects. Although phytonanotherapy has not been explored in the clinical treatment of MASLD/MASH, MNPs such as gold NPs (AuNPs) and silver NPs (AgNPs) have been reported to improve metabolic processes by reducing blood glucose levels, body fat, and inflammation. Therefore, these actions suggest that MNPs can potentially be used in the treatment of MASLD/MASH and related metabolic diseases. Further studies are warranted to investigate the feasibility and efficacy of phytonanomedicine before clinical application.

Long Noncoding RNAs in Diet-Induced Metabolic Diseases.

The prevalence of metabolic diseases, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), is steadily increasing. Although many risk factors, such as obesity, insulin resistance, or hyperlipidemia, as well as several metabolic gene programs that contribute to the development of metabolic diseases are known, the underlying molecular mechanisms of these processes are still not fully understood. In recent years, it has become evident that not only protein-coding genes, but also noncoding genes, including a class of noncoding transcripts referred to as long noncoding RNAs (lncRNAs), play key roles in diet-induced metabolic disorders. Here, we provide an overview of selected lncRNA genes whose direct involvement in the development of diet-induced metabolic dysfunctions has been experimentally demonstrated in suitable in vivo mouse models. We further summarize and discuss the associated molecular modes of action for each lncRNA in the respective metabolic disease context. This overview provides examples of lncRNAs with well-established functions in diet-induced metabolic diseases, highlighting the need for appropriate in vivo models and rigorous molecular analyses to assign clear biological functions to lncRNAs.

Common dietary emulsifiers promote metabolic disorders and intestinal microbiota dysbiosis in mice.

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

Body Composition in Patients With Metabolic Dysfunction-associated Steatotic Liver Disease: Impact of Body Surface Area.

BACKGROUND/AIM: To examine the relationship between the body surface area (BSA) and body composition in patients with metabolic dysfunction-associated steatotic liver disease (MASLD, 2,141 men and 986 women). MATERIALS AND METHODS: BSA and body composition parameters were examined. RESULTS: The median body mass index (BMI) was 25.0 kg/m2 for both men and women (p=0.7754). The median body surface area (BSA) was 1.854 m2 for men and 1.618 m2 for women (p<0.0001). In men, the median fat mass was 17.7 kg, whereas in women, it was 22.1 kg (p<0.0001). Additionally, the median fat-free mass was 55.4 kg in men and 39.3 kg in women (p<0.0001).). In male cases, BSA significantly correlated with fat mass (r=0.82, p<0.0001) and fat-free mass (r=0.95, p<0.0001). In female cases, BSA significantly correlated with fat mass (r=0.87, p<0.0001) and fat-free mass (r=0.94, p<0.0001). CONCLUSION: BSA could be a useful marker for the estimation of body composition in patients with MASLD.

Modulation of gut microbiota by crude gac aril polysaccharides ameliorates diet-induced obesity and metabolic disorders.

Obesity is a global health challenge that causes metabolic dysregulation and increases the risk of various chronic diseases. The gut microbiome is crucial in modulating host energy metabolism, immunity, and inflammation and is influenced by dietary factors. Gac fruit (Momordica cochinchinensis), widely consumed in Southeast Asia, has been proven to have various biological activities. However, the composition and effect of crude gac aril polysaccharides (GAP) on obesity and gut microbiota disturbed by high-fat diet (HFD) remain to be elucidated. Compositional analysis showed that GAP contains high oligosaccharides, with an average of 7-8 saccharide units. To mimic clinical obesity, mice were first made obese by feeding HFD for eight weeks. GAP intervention was performed from week 9 to week 20 in HFD-fed mice. Our results showed that GAP inhibited body weight gain, eWAT adipocyte hypertrophy, adipokine derangement, and hyperlipidemia in HFD-induced obese mice. GAP improved insulin sensitivity, impaired glucose tolerance, and hepatic steatosis. GAP modulated the gut microbiota composition and reversed the HFD-induced dysbiosis of at least 20 genera. Taken together, GAP improves metabolic health and modulates the gut microbiome to relieve obesity risk factors, demonstrating the potential of dietary GAP for treating obesity-associated disorders.

Peripheral inflammatory hyperalgesia is exacerbated in rats with metabolic disorders induced by a fructose diet.

This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with the von Frey test and measuring paw edema to assess inflammatory responses. Wistar rats were administered water or 10% fructose solution ad libitum over a period of 5 weeks. After intraplantar administration of inflammatory agents such as carrageenan (1 mg/paw), lipopolysaccharide (LPS; 100 µg/paw), or prostaglandin E2 (PGE2, 100 ng/paw), we conducted mechanical hyperalgesia tests and paw edema evaluations. The fructose diet resulted in dyslipidemia, elevated insulin and leptin plasma levels, insulin resistance, and increased epididymal and retroperitoneal adiposity compared to control animals. In response to inflammatory agents, the fructose group displayed significantly enhanced peripheral hyperalgesia and more pronounced paw edema. Our results demonstrate that fructose not only contributes to the development of obesity and metabolic disorder but also exacerbates peripheral inflammatory pain responses by enhancing prostaglandin sensitivity.

Adipose Tissue Immunometabolism: Unveiling the Intersection of Metabolic and Immune Regulation.

UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).

The impact of a western diet on gut microbiota and circadian rhythm: A comprehensive systematic review of in vivo preclinical evidence.

AIMS: Here, we present a systematic review that compiles in vivo experimental data regarding the effect of the WD on the gut microbiota and its impact on the circadian rhythm. Additionally, we reviewed studies evaluating the combined effects of WD and circadian cycle disruption on gut microbiota and circadian cycle markers. MATERIALS AND METHODS: The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. KEY FINDINGS: Preclinical studies revealed that WD triggers circadian rhythmicity disruption, reduces the alpha-diversity of the microbiota and favors the growth of bacterial groups that are detrimental to intestinal homeostasis, such as Clostridaceae, Enterococcus, Parasutterella and Proteobacteria. When the WD is combined with circadian clock disruption, gut dysbiosis become more pronounced. Reduced cycling of Per3, Rev-erb and CLOCK in the intestine, which are related to dysregulation of lipid metabolism and potential metabolic disease, was observed. SIGNIFICANCE: In conclusion, current evidence supports the potential of WD to trigger microbiota dysregulation, disrupt the biological clock, and increase susceptibility to metabolic disorders and potentially chronic diseases.