Search Results (85)

Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, chronic low-grade inflammation, and progressive metabolic dysfunction affecting multiple organs. This review explores the molecular and physiological mechanisms underlying T2DM, emphasizing the role of intracellular metabolic signaling pathways, mitochondrial function, and inter-organ communication in the development and progression of metabolic dysregulation. Particular attention is given to key regulatory pathways such as AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin (mTOR), which play central roles in cellular energy sensing, glucose metabolism, and lipid homeostasis. Dysregulation of these pathways contributes to impaired insulin signaling, mitochondrial dysfunction, oxidative stress, and altered adipogenesis, all of which are critical factors in the pathophysiology of T2DM. In addition, growing evidence highlights the importance of metabolic crosstalk between skeletal muscle, adipose tissue, liver, pancreas, and the gut microbiota through signaling molecules including adipokines, myokines, hepatokines, and gut-derived metabolites. These inter-organ networks influence systemic inflammation, metabolic flexibility, and glucose homeostasis. Lifestyle factors such as physical activity, nutritional patterns, and micronutrient status have also been shown to modulate these molecular pathways, improving mitochondrial function and insulin sensitivity while reducing inflammatory signaling. Despite significant advances in understanding the molecular basis of T2DM, important challenges remain, including heterogeneity in disease progression and variability in individual metabolic responses. In conclusion, T2DM should be understood as a multisystem metabolic disorder driven by complex interactions between molecular signaling pathways and systemic metabolic regulation. Future research integrating molecular mechanisms with clinical and lifestyle interventions may help develop more effective strategies for prevention and treatment. Full article

Background/Objectives: C1q/TNF-related protein 3 (CTRP3), progranulin (PGRN), and chemerin are adipokines that participate in systemic inflammation. This study systematically examined adipokine levels in cystic fibrosis patients of different ages to evaluate their role in inflammatory, metabolic, and hepatic processes. Thirty-seven pediatric and thirty-three adult CF patients were enrolled to assess the potential of these adipokines as biomarkers. Methods: Anthropometric and physiological data, pulmonary function (forced expiratory volume, FEV1; vital capacity, VC), and liver fibrosis score FIB-4 were assessed. Liver stiffness was measured by transient elastography. Serum samples from 40 healthy adult volunteers served as the control group. Serum concentrations of chemerin, CTRP3, and PGRN were quantified by enzyme-linked immunosorbent assay (ELISA). Results: Compared with healthy controls, adults with CF had markedly lower circulating CTRP3 levels, whereas PGRN concentrations were significantly higher. Among CF patients, both CTRP3 and PGRN were higher in the pediatric group than in adults, while chemerin did not vary with age. The presence of cystic fibrosis-related liver disease (CFLD) did not significantly alter adipokine levels relative to CF patients without liver disease. Receiver operator characteristic (ROC) analysis showed that circulating PGRN could reliably differentiate CF patients from controls; none of the three adipokines predicted the presence of CFLD. CTRP3 and PGRN were inversely correlated with age, BMI, and pulmonary function. Conclusions: Overall, our data support systemic PGRN as a potential biomarker for CF and indicate an age-dependent regulation of circulating CTRP3 and PGRN. Both proteins were inversely associated with BMI, inflammatory markers, liver fibrosis, and pulmonary capacity. Full article

Population aging and widespread sedentary lifestyles have increased the prevalence of chronic non-communicable diseases, many of which are linked to progressive disruptions of cellular homeostasis. Autophagy, a conserved cellular degradation and recycling pathway, plays a central role in maintaining metabolic flexibility, proteostasis, and organ function. However, aging and physical inactivity impair autophagic regulation, thereby contributing to the development of sarcopenia, cardiovascular diseases, metabolic disorders, and neurodegenerative diseases. Physical exercise is a non-pharmacological intervention that can restore autophagic activity and confer systemic health benefits in multiple preclinical and clinical contexts. Increasing evidence indicates that these benefits are mediated not only by local tissue adaptations but also by complex inter-organ communication. Central to this process are exercise-induced bioactive factors, collectively termed exerkines, including myokines, cardiokines, adipokines, hepatokines, osteokines, and circulating miRNAs. Rather than acting independently, exerkines form an integrated signaling network that fine-tunes autophagic flux across multiple tissues. Exerkine-mediated regulation of autophagy involves key pathways such as AMPK/mTOR, FoxO, SIRT1, ULK1, and TFEB, thereby coordinating energy metabolism, mitochondrial quality control, inflammation, and protein turnover in skeletal muscle, heart, liver, adipose tissue, bone, and the central nervous system. This review summarizes current evidence on representative exerkines and their roles in autophagy-dependent inter-organ crosstalk, highlighting the exercise–exerkine–autophagy axis as a promising target for preventing and managing chronic diseases. Full article

Metabolic inflammation, a state of chronic low-grade inflammation linked to insulin resistance, plays a central role in the development of obesity-related conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders. In recent years, two molecules have gained significant prominence in this field, owing to their mechanistic involvement in metabolic inflammation and insulin resistance: fetuin-A (FetA), aliver-derived hepatokine, and chymase, a serine protease released from mast cells. Although they arise from distinct biological sources, they converge on overlapping inflammatory and metabolic pathways. FetA acts as an endogenous ligand for Toll-like receptor 4 (TLR4), activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, driving proinflammatory cytokine release, and impairing insulin signaling. Chymase, on the other hand, generates angiotensin II and activates transforming growth factor-β (TGF-β), thereby promoting oxidative stress, fibrosis, and secondary metabolic dysfunction. This review proposes a conceptual dual-target framework in which FetA and chymase are considered complementary, rather than independent, mediators of metabolic inflammation. Importantly, this framework is not intended to supersede other established pathways implicated in metabolic inflammation, but rather to provide an integrative perspective that complements existing hepatokine and immune-centered models. Their convergence on NF-κB and TGF-β signaling pathways highlights shared mechanistic nodes within metabolic inflammation. Accordingly, the emphasis of this review is on mechanistic integration within metabolic inflammation, rather than on immediate therapeutic innovation or clinical translation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic condition with a complex pathophysiology involving multiple organs. Organokines, including hepatokines, myokines, cardiokines, renokines, osteokines, and adipokines, play central roles in lipid metabolism, glucose homeostasis, inflammation, and fibrosis. Dysregulation of these signaling molecules contributes to the progression of MASLD and its systemic complications. This review examines the role of organokine-mediated crosstalk between the liver and peripheral organs (e.g., muscle, heart, kidneys, bone, and adipose tissue) in the pathogenesis of MASLD. Key molecules, such as myostatin, FGF-21, IL-6, and adiponectin, influence insulin sensitivity, lipid metabolism, and inflammation. Some organokines have protective effects (e.g., FGF-21, irisin, and klotho), while others, such as myostatin and fetuin-A, exacerbate insulin resistance and fibrosis. These findings suggest that targeting organokines could provide potential biomarkers and therapeutic strategies for MASLD. Future research should focus on elucidating the molecular mechanisms and assessing the role of organokines in the prevention and treatment of MASLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as a systemic condition that is associated with an increased prevalence of chronic kidney disease (CKD), independent of classical risk factors. This review explores MASLD and metabolic kidney dysfunction, emphasizing lipotoxicity, emerging biomarkers, and liver–kidney fat imaging techniques. Renal fat is discussed as an ectopic lipid depot that may contribute to kidney vulnerability in the same cardiometabolic milieu as MASLD. In this context, lipotoxicity, a phenomenon intensively studied in MASLD, can affect multiple nephron segments, promoting fibrosis and, ultimately, CKD. Hepatokines may support the concept of a liver–kidney metabolic axis, but human data remain limited. Tubular biomarkers show promise for detecting early renal injury, but lack validation in large populations. Hepatic steatosis is quantified through multiple validated imaging techniques such as ultrasound, elastography, and magnetic resonance imaging (MRI). In contrast, renal fat imaging studies are limited and heterogeneous, and still lack standardization. In MASLD, an integrated hepatorenal assessment is warranted to capture the full burden of the disease. Full article

The inflammatory and metabolic complexity of colitis necessitates therapies that act on multiple immune pathways. Using serum proteomic profiling, the present study evaluated the systemic immunomodulatory profile of Epilobium angustifolium lyophilized methanol-aqueous extract rich in oenothein B (EAE) in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis in a comparative manner to dexamethasone (DXM). DSS exposure triggered robust inflammatory activation, evidenced by elevated chemokines (CXCL9, CXCL10, CCL11), proinflammatory cytokines (IL-1α, IL-12, PAI-1, RAGE) and metabolic stress mediators (leptin, resistin, FGF-21). Treatment with EAE significantly attenuated this inflammatory profile, notably reducing Th2-skewed chemokines and eosinophil recruitment. In contrast to DXM, EAE uniquely normalized pro-thrombotic and tissue-remodeling markers, including PAI-1 and RAGE, both implicated in intestinal barrier dysfunction and chronic inflammation. Furthermore, EAE demonstrated superior modulation of inflammation-associated growth factors (IGFBP-5, HGF, Flt3L) and adipokines (leptin, resistin), indicating a broader therapeutic scope that includes metabolic dysfunctions. Collectively, our data reveal that EAE exerts a distinct immunoregulatory profile, modulating both innate and adaptive immune pathways while simultaneously addressing metabolic pathologies. These multifaceted actions underscore its promise as a phytotherapeutic candidate for the management of ulcerative colitis and other inflammatory conditions, with potential advantages over conventional steroid treatment. Full article

Background: Fetuin-A, a hepatokine implicated in metabolic regulation, has been associated with both metabolic syndrome and cardiovascular disease. However, its specific role in type 2 diabetes mellitus (T2DM) remains incompletely understood. Objective: This study aimed to investigate the relationship between fetuin-A levels and key components of metabolic syndrome (abdominal obesity, arterial hypertension, hyperglycemia, hypertriglyceridemia and low high-density lipoprotein cholesterol) as well as other cardiovascular risk markers, including metabolic dysfunction-associated fatty liver disease (MAFLD), carotid intima-media thickness (CIMT), and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Methods: A total of 51 patients with T2DM not receiving insulin therapy were enrolled. Participants underwent clinical, biochemical, and imaging evaluations. Hepatic steatosis was assessed via abdominal ultrasonography, and subclinical atherosclerosis was evaluated using CIMT measured with Doppler ultrasonography. Serum fetuin-A was quantified by ELISA. Results: Hepatic steatosis was significantly associated with metabolic syndrome, increased CIMT, and dyslipidemia (elevated total cholesterol, triglycerides, and reduced HDL cholesterol). Although no direct correlation was found between fetuin-A levels and hepatic steatosis, multivariate analysis revealed that fetuin-A concentrations were significantly influenced by total cholesterol and LDL cholesterol levels. Conclusions: Fetuin-A appears to be linked to lipid abnormalities in T2DM and may contribute to cardiovascular risk in this population. These findings support the potential utility of fetuin-A as a biomarker and possible therapeutic target for dyslipidemia management in diabetic patients. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge characterized by complex adipose–liver interactions mediated by adipokines and hepatokines. Despite rapid field evolution, a comprehensive understanding of research trends and translational advances remains fragmented. This study systematically maps the scientific landscape through bibliometric analysis, identifying emerging domains and future clinical translation directions. Methods: A comprehensive bibliometric analysis of 1002 publications from 2004 to 2025 was performed using thematic mapping, temporal trend evaluation, and network analysis. Analysis included geographical and institutional distributions, thematic cluster identification, and research paradigm evolution assessment, focusing specifically on adipokine–hepatokine signaling mechanisms and clinical implications. Results: The United States and China are at the forefront of research output, whereas European institutions significantly contribute to mechanistic discoveries. The thematic map analysis reveals the motor/basic themes residing at the heart of the field, such as insulin resistance, fatty liver, metabolic syndrome, steatosis, fetuin-A, and other related factors that drive innovation. Basic clusters include metabolic foundations (obesity, adipose tissue, FGF21) and adipokine-centered subjects (adiponectin, leptin, NASH). New themes focus on inflammation, oxidative stress, gut microbiota, lipid metabolism, and hepatic stellate cells. Niche areas show targeted fronts such as exercise therapies, pediatric/novel adipokines (chemerin, vaspin, omentin-1), and advanced molecular processes that focus on AMPK and endoplasmic-reticulum stress. Temporal analysis shows a shift from single liver studies to whole models that include the gut microbiota, mitochondrial dysfunction, and interactions between other metabolic systems. The network analysis identifies nine major clusters: cardiovascular–metabolic links, adipokine–inflammatory pathways, hepatokine control, and new therapeutic domains such as microbiome interventions and cellular stress responses. Conclusions: In summary, this study delineates current trends and emerging areas within the field and elucidates connections between mechanistic research and clinical translation to provide guidance for future research and development in this rapidly evolving area. Full article

Background and aim: ANGPTL3 is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL) through its N-terminal domain. Besides this activity, the C-terminal domain of ANGPTL3 interacts with integrin αVβ3. Since integrins are involved in inflammation and in the initiation of atherosclerotic plaque, the aim of our study was to evaluate the potential direct pro-inflammatory action of ANGPTL3 through the interaction of the fibrinogen-like domain and integrin αVβ3. Methods: We utilized cultured THP-1 human-derived macrophages and evaluated their pro-inflammatory phenotype in response to treatment with human recombinant ANGPTL3 (hANGPTL3). By Western blot, RT-qPCR, biochemical analysis, and ELISA assays, we determined the expression of genes and proteins involved in lipid metabolism and inflammatory response as well as intracellular cholesterol and triglyceride levels. In addition, we evaluated the effect of hANGPTL3 on the cellular cholesterol efflux process. Results: Incubation of THP-1-derived macrophages with 100 ng/mL of hANGPTL3 increased the mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNFα (respectively, 1.87 ± 0.08-fold, 1.35 ± 0.11-fold, and 2.49 ± 0.43-fold vs. control). The secretion of TNFα, determined by an ELISA assay, was also induced by hANGPTL3 (1.98 ± 0.4-fold vs. control). The pro-inflammatory effect of hANGPTL3 was partially counteracted by co-treatment with the integrin αVβ3 inhibitor RGD peptide, reducing the mRNA levels of IL-1β (3.35 ± 0.35-fold vs. 2.54 ± 0.25-fold for hANGPTL3 vs. hANGPTL3 + RGD, respectively). Moreover, hANGPTL3 reduced cholesterol efflux to apoA-I, with a parallel increase in the intracellular triglyceride and cholesterol contents by 31.2 ± 2.8% and 20.0 ± 4.1%, respectively, compared to the control. Conclusions: ANGPTL3 is an important liver-derived regulator of plasma lipoprotein metabolism, and overall, our results add a new important pro-inflammatory activity of this circulating protein. This new function of ANGPTL3 could also be related to triglyceride and cholesterol accumulation into macrophages. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Background and Objectives: Fetuin-A is mostly synthesized in the liver. It is a hepatokine, which is an extracellular inhibitor of growth factors. There is a scarcity of data on the clinical utility of serum fetuin-A (SFA) in alcohol-associated cirrhosis (AC). We first investigated the association between SFA levels and disease phenotypes in alcoholic liver disease (ALD) patients, including alcohol-associated steatotic liver (ASL) and alcohol-associated hepatitis (AH), along with AC patients. Materials and Methods: There were 26 healthy controls and 64 ALD patients in this case–control study. The severity of the disease in the AC patients was evaluated using the Child–Pugh classification (CPC-A, -B, and -C), and the FH and AC patients’ Maddrey’s differential function scores and the Model of End-Stage Liver Disease Sodium (MELD-Na) scores were computed. We measured SFA levels using a human fetuin-A enzyme-linked immunosorbent assay (ELISA) kit. Results: The SFA concentrations were lower in the AC group and higher in the ASL group [670.72 (412.36) mg/L vs. 1484.61 (858.16) mg/L, respectively; p < 0.001]. When compared to patients with ASL, the SFA levels in AC patients were noticeably lower. However, similar SFA levels were observed for the AH group and the healthy controls, as well as for the ASL group and the healthy controls. Within the AC group, the CPC-A subgroup had the highest median SFA values, while the CPC-C subgroup had the lowest median SFA value. Furthermore, the median SFA levels demonstrated significant and inverse correlations with the CPC scores and the MELD-Na scores (rho = −0.671, p < 0.001; rho = −0.742, p < 0.001, respectively). A negative correlation was observed between the SFA levels and the MELD-Na scores in the AH group (ρ = −0.621, p = 0.013). Conclusions: In ALD patients, decreased SFA levels, which exhibit disease severity, might be an auxiliary biomarker for the follow-up of AC patients. Full article

Exercise suppresses appetite in individuals with obesity irrespective of the type, duration, or intensity of the exercise. This effect is mediated through various physiological and biochemical mechanisms. Exercise influences appetite-regulatory hormones such as ghrelin and leptin, reducing hunger signals. Additionally, exercise generates metabolites and myokines, along with hepatokines, which modulate appetite suppression. Brain-derived neurotrophic factor (BDNF) is also implicated in modulating appetite. Changes in eating behaviors, gastric motility, and gastric emptying further contribute to a reduced appetite. Mental stress and body temperature alterations during exercise can also impact hunger levels. This review synthesizes current evidence and provides specific biochemical, metabolic and molecular mechanisms of how exercise and obesity affect appetite regulation. More specifically, it is extensively discussed the effect of exercise and obesity on: (1) endocrine mediators (hepatokines, metabolites, myokines, and neurotrophins); (2) physiological modulators (gastric emptying and body temperature); and (3) behavioral influences (eating patterns and visual food cues) in association with appetite regulation. Collectively, these factors highlight the complex interplay between physical activity and appetite regulation, offering insights into potential therapeutic strategies for managing obesity through exercise. Full article

Background and Aims: Hepatokines have a regulatory function in adipose tissue inflammation, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular diseases, and atherosclerosis. Our aim was to evaluate the profile of proinflammatory cytokines and hepatokines in patients with MASLD and carotid atherosclerosis (CA). Methods: A prospective and basic research study was conducted on patients with MASLD. Clinical data were collected from a detailed medical history. Liver stiffness was measured using transient elastography, and carotid Doppler ultrasound was performed. Levels of basic biochemical parameters, systemic inflammation markers (TNF-α, IL-6, IL-10, IL-18), and hepatokines (FGF21, ANGPTL4, fetuin-A) were determined. The results were analyzed with SPSS v22.0 software. Results: Sixty-seven patients with MASLD were included, 72.1% were women, and the mean patient age was 53.9 + 11.3 years. Atherosclerosis was found in 11 patients (16.2%), and carotid intima–media thickness (CIMT) was altered in the right carotid of 13 patients (19.1%), in the left carotid of 19 (27.9%), and bilaterally in 7 (10.3%). Greater age (p = 0.001) and high blood pressure (p = 0.028) were correlated with atherosclerosis. There were no differences in systemic inflammation markers, and the hepatokines FGF21 and fetuin-A tended to increase in the presence of CIMT and CA alterations, regardless of fibrosis. Conclusions: In our population, patients with MASLD had a 16.6% prevalence of CA, and the risk increased with age and a history of high blood pressure. FGF21 tended to increase in patients with MASLD + atherosclerosis, and fetuin-A was correlated with CIMT alterations, suggesting that the combination of these markers could guide us to suspect early endothelial alterations in patients with MASLD. Full article

Background/Objective: Leukocyte cell-derived chemotaxin-2 (LECT2), a hepatokine, is implicated in non-alcoholic fatty liver disease (NAFLD). Although NAFLD and sarcopenia are closely linked, the relationship between plasma LECT2 levels and sarcopenia remains unclear. Methods: We analyzed plasma LECT2 levels in 400 older adults aged 70–84 years old living in the community enrolled in the Korean Frailty and Aging Cohort Study. The appendicular skeletal muscle mass (ASM) and handgrip strength (HGS), both adjusted for the BMI, were used to evaluate the muscle mass and strength. A low muscle mass (LMM) was defined using the sex-specific lowest quintile of ASM/BMI as the cutoff value, while a low muscle strength (LMS) was determined based on the lowest quintile of the HGS/BMI. Sarcopenia was defined by the coexistence of an LMM and LMS. Results: NAFLD was identified using a fatty liver index > 30. The participants with NAFLD had significantly higher plasma LECT2 levels compared to their non-NAFLD counterparts (34.4 [29.3–41.1] vs. 29.0 [24.7–36.7] ng/mL, p < 0.001). Circulating LECT2 levels were inversely correlated with ASM/BMI (r = −0.506, p < 0.001) and HGS/BMI (r = −0.474, p < 0.001), as determined by Spearman correlation analysis. Among the study participants, 79 (19.8%) were categorized as having either an LMM or LMS, and 31 (7.8%) were identified as having sarcopenia. In multivariate logistic regression, the highest LECT2 quartile had markedly greater odds of an LMM (OR 3.31, 95% CI 1.41–7.75), LMS (OR 2.85, 95% CI 1.29–6.26), and sarcopenia (OR 5.48, 95% CI 1.57–19.05) relative to the lowest quartile. Conclusions: Our results indicate that elevated plasma LECT2, a hepatokine increased in NAFLD, contributes to an increased risk of sarcopenia in older adults. Full article