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.

Impact of metabolic phenotype and alcohol consumption on mortality risk in metabolic dysfunction-associated fatty liver disease: a population-based cohort study.

Patients with metabolic dysfunction-associated fatty liver disease (MAFLD) often present with concomitant metabolic dysregulation and alcohol consumption, potentially leading to distinct clinical outcomes. We analyzed data from 8043 participants with MAFLD in the Thai National Health Examination Survey with linked mortality records. According to the MAFLD criteria, 1432 individuals (17.2%) were categorized as having the diabetes phenotype, 5894 (71.0%) as the overweight/obesity phenotype, and 978 (11.8%) as the lean metabolic phenotype. Over 71,145 person-years, 916 participants died. Using Cox proportional hazard models adjusting for physiological, lifestyle, and comorbid factors, both diabetes (adjusted hazards ratio [aHR] 1.59, 95% CI 1.18-2.13) and lean metabolic phenotypes (aHR 1.28, 95% CI 1.01-1.64) exhibited significantly higher mortality risk compared to the overweight/obesity phenotype. A J-shaped relationship was observed between daily alcohol consumption and the risk of all-cause mortality. Daily alcohol intake exceeding 50 g for women and 60 g for men increased the all-cause mortality risk among MAFLD individuals with the lean metabolic phenotype (aHR 3.39, 95% CI 1.02-11.29). Our study found that metabolic phenotype and alcohol consumption have interactive effects on the risk of all-cause mortality in patients with MAFLD, indicating that evaluating both factors is crucial for determining prognostic outcomes and management strategies.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

Interaction of serotonin/GLP-1 circuitry in a dual preclinical model for psychiatric disorders and metabolic dysfunction.

Isolation of rodents throughout adolescence is known to induce many behavioral abnormalities which resemble neuropsychiatric disorders. Separately, this paradigm has also been shown to induce long-term metabolic changes consistent with a pre-diabetic state. Here, we investigate changes in central serotonin (5-HT) and glucagon-like peptide 1 (GLP-1) neurobiology that dually accompany behavioral and metabolic outcomes following social isolation stress throughout adolescence. We find that adolescent-isolation mice exhibit elevated blood glucose levels, impaired peripheral insulin signaling, altered pancreatic function, and fattier body composition without changes in bodyweight. These mice further exhibited disruptions in sleep and enhanced nociception. Using bulk and spatial transcriptomic techniques, we observe broad changes in neural 5-HT, GLP-1, and appetitive circuits. We find 5-HT neurons of adolescent-isolation mice to be more excitable, transcribe fewer copies of Glp1r (mRNA; GLP-1 receptor), and demonstrate resistance to the inhibitory effects of the GLP-1R agonist semaglutide on action potential thresholds. Surprisingly, we find that administration of semaglutide, commonly prescribed to treat metabolic syndrome, induced deficits in social interaction in group-housed mice and rescued social deficits in isolated mice. Overall, we find that central 5-HT circuitry may simultaneously influence mental well-being and metabolic health in this model, via interactions with GLP-1 and proopiomelanocortin circuitry.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.

Beyond blood pressure, fluid and electrolyte homeostasis - Role of the renin angiotensin aldosterone system in the interplay between metabolic diseases and breast cancer.

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.

Postbiotics as Metabolites and Their Biotherapeutic Potential.

This review highlights the role of postbiotics, which may provide an underappreciated avenue doe promising therapeutic alternatives. The discovery of natural compounds obtained from microorganisms needs to be investigated in the future in terms of their effects on various metabolic disorders and molecular pathways, as well as modulation of the immune system and intestinal microbiota in children and adults. However, further studies and efforts are needed to evaluate and describe new postbiotics. This review provides available knowledge that may assist future research in identifying new postbiotics and uncovering additional mechanisms to combat metabolic diseases.

Metabolic disorders induced the changes in the expressions of TNFα, E-cadherin and ultrastructural alteration of liver cells in a typical animal model of type 2 diabetes: Psammomys obesus.

By using a unique animal model of type 2 diabetes mellitus, Psammomys obesus induced by a high-calorie diet (HCD) for nine months, we showed for the first time, in the liver, the impact of inflammation on the remodeling of intercellular junction molecules E-cadherins during the progression of steatohepatitis. Under the effect of HCD, the expressions of immunohistochemical markers, Tumor Necrosis Factor alpha (TNFα) and E-cadherins were inversely correlated. Ultrastructural examination revealed the involvement of destabilization and loss of E-cadherins in the process of hepatic pathogenesis. This mechanical maintenance stress was favored by the recruitment of immune cells which contributed to the triggering and progression of fibrosis by the enlargement of the intercellular space and the invasion of collagen fibers. Furthermore to escape cell death, loss of E-cadherins played a major role in mediating fibrosis. Psammomys obesus is a promising model for experimental research, enabling the extrapolation of observed structural and functional alterations in humans, the objective to find new therapeutic targets. The physiological resemblance between Psammomys obesus and humans enhances the precision and relevance of biomedical research efforts.

Lactate-induced lactylation and cardiometabolic diseases: From epigenetic regulation to therapeutics.

Cardiometabolic diseases (CMDs) denote a cadre of chronic and devastating cardiovascular anomalies routed from metabolic derangements including obesity, type 2 diabetes mellitus, and hypertension. Recent studies have demonstrated the association between histone lactylation, a unique form of post-translational modification, and pathogenesis of CMDs, apparently through epigenetic mechanisms. Lactylation has been indicated to regulate key aspects of metabolism, inflammation, and cardiovascular function in the realm of CMDs in a cellular and tissue-specific manner. A better understanding of the molecular, cellular and physiological domains of lactylation in the etiology of CMDs is expected to offer new insights into etiopathogenesis, hazardous factor control and therapeutic development for these challenging ailments.

GPR41 and GPR43: From development to metabolic regulation.

G-protein-coupled receptors are a diverse class of cell surface receptors that orchestrate numerous physiological functions. The G-protein-coupled receptors, GPR41 and GPR43, sense short-chain fatty acids (SCFAs), which are metabolites of dietary fermentation by the host's intestinal bacteria. These receptors have gained attention as potential therapeutic targets against various diseases because of their SCFA-mediated beneficial effects on the host's intestinal health. Mounting evidence has associated the activity of these receptors with chronic metabolic diseases, including obesity, diabetes, inflammation, and cardiovascular disease. However, despite intensive research using various strategies, including gene knockout (KO) mouse models, evidence about the precise roles of GPR41 and GPR43 in disease treatment remains inconsistent. Here, we comprehensively review the latest findings from functional studies of the signaling mechanisms that underlie the activities of GPR41 and GPR43, as well as highlight their multifaceted roles in health and disease. We anticipate that this knowledge will guide future research priorities and the development of effective therapeutic interventions.

Gut-bacteria derived membrane vesicles and host metabolic health: a narrative review.

The intestinal microbiota, consisting of an estimated 10^10-10^11 organisms, regulate physiological processes involved in digestion, metabolism, and immunity. Surprisingly, these intestinal microorganisms have been found to influence tissues that are not directly in contact with the gut, such as adipose tissue, the liver, skeletal muscle, and the brain. This interaction takes place even when intestinal barrier function is uncompromised. An increasing body of evidence suggests that bacterial membrane vesicles (bMVs), in addition to bacterial metabolites such as short-chain fatty acids, are able to mediate effects of the microbiota on these host tissues. The ability of bMVs to dissipate from the intestinal lumen into systemic circulation hereby facilitates the transport and presentation of bacterial components and metabolites to host organs. Importantly, there are indications that the interaction between bMVs and tissues or immune cells may play a role in the etiology of (chronic metabolic) disease. For example, the gut-derived bMV-mediated induction of insulin resistance in skeletal muscle cells and pro-inflammatory signaling by adipocytes possibly underlies diseases such as type 2 diabetes and obesity. Here, we review the current knowledge on bMVs in the microbiota's effects on host energy/substrate metabolism with a focus on etiological roles in the onset and progression of metabolic disease. We furthermore illustrate that vesicle production by bacterial microbiota could potentially be modulated through lifestyle intervention to improve host metabolism.

A comprehensive study on the regulation of Compound Zaoren Granules on cAMP/CREB signaling pathway and metabolic disorder in CUMS-PCPA induced insomnia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood. AIM OF THE STUDY: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles. METHODS: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated. RESULTS: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted. CONCLUSION: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.

Mitigation of CXCL10 secretion by metabolic disorder drugs in microglial-mediated neuroinflammation.

Metabolic disorders are associated with several neurodegenerative diseases. We previously identified C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon gamma-induced protein 10 (IP-10), as a major contributor to the type I interferon response in microglial-mediated neuroinflammation. Therefore, we hypothesized FDA-approved metabolic disorder drugs that attenuate CXCL10 secretion may be repurposed as a treatment for neurodegenerative diseases. Screening, dose curves, and cytotoxicity assays in LPS-stimulated microglia yielded treprostinil (hypertension), pitavastatin (hyperlipidemia), and eplerenone (hypertension) as candidates that significantly reduced CXCL10 secretion (in addition to other pro-inflammatory mediators) without impacting cell viability. Altogether, these data suggest metabolic disorder drugs that attenuate CXCL10 as potential treatments for neurodegenerative disease through mitigating microglial-mediated neuroinflammation.

TNIK's emerging role in cancer, metabolism, and age-related diseases.

Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries. We also highlight how TNIK's role in many biological processes converges upon several hallmarks of aging. We conclude by discussing the therapeutic landscape of TNIK-targeting drugs and the recent success of clinical trials targeting TNIK.

Digital twins and artificial intelligence in metabolic disease research.

Digital twin technology is emerging as a transformative paradigm for personalized medicine in the management of chronic conditions. In this article, we explore the concept and key characteristics of a digital twin and its applications in chronic non-communicable metabolic disease management, with a focus on diabetes case studies. We cover various types of digital twin models, including mechanistic models based on ODEs, data-driven ML algorithms, and hybrid modeling strategies that combine the strengths of both approaches. We present successful case studies demonstrating the potential of digital twins in improving glucose outcomes for individuals with T1D and T2D, and discuss the benefits and challenges of translating digital twin research applications to clinical practice.

Inhibition of activin receptor 2 signalling ameliorates metabolic dysfunction-associated steatotic liver disease in western diet/L-NAME induced cardiometabolic disease.

OBJECTIVE: Blockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Mice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). RESULTS: sACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. CONCLUSIONS: Blockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.

Bile acid metabolism in health and ageing-related diseases.

Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.