BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood...BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood. In this study, we aimed to investigate the role of CCL20 in MASH progression. METHODS: Using RNA sequencing data and murine models of MASH, we analyzed the expression levels of CCL20 in liver tissues, as well as the correlation of CCL20 levels with liver function parameters. Hepatic CCL20-knockdown and hepatic progenitor cell (HPC)/cholangiocyte-specific CCL20-knockout mice were used to assess the role of CCL20 in hepatic steatosis and inflammation. The mechanisms by which CCL20 influences MASH were explored via in vitro and in vivo gain- and loss-of-function approaches. RESULTS: We observed that CCL20 is significantly upregulated in MASH livers from mice and humans and that hepatic CCL20 expression is positively correlated with MASH severity. CCL20, which is mainly produced by HPCs/cholangiocytes, is transcriptionally activated by RELB and SOX9. In mice, CCL20 knockout in HPCs/cholangiocytes attenuated pathological changes in the liver. Mechanistically, by binding to CCR6, CCL20 activates the JNK signaling pathway, which increases OLR1 expression, thereby promoting oxLDL uptake and cholesterol deposition in hepatocytes. CONCLUSION: These findings implicate the CCL20-CCR6-JNK-OLR1 axis as a crucial determinant of MASH progression and highlight CCL20 inhibition as an attractive therapeutic strategy for MASH.
Treatment of symptomatic/advanced heart failure (HF) in patients who also have chronic kidney disease (CKD) and type 2 diabetes (T2D) may include a steroidal mineralocorticoid receptor antagonist (MRA). However, patients...Treatment of symptomatic/advanced heart failure (HF) in patients who also have chronic kidney disease (CKD) and type 2 diabetes (T2D) may include a steroidal mineralocorticoid receptor antagonist (MRA). However, patients with CKD and T2D who are at high risk of developing HF may benefit from taking the nonsteroidal MRA finerenone. Results from phase 3 placebo-controlled trials of finerenone in patients with CKD associated with T2D showed that finerenone (plus a renin-angiotensin-aldosterone system inhibitor) reduced the risk of new-onset HF, improved other HF outcomes, and caused a significant slowing of CKD progression. Those who work in cardiology need to be aware of the HF risk-reduction effects of finerenone in patients with CKD and T2D. In this review, we provide a rationale for finerenone use in cardiology based on the available finerenone clinical trial data and from the perspective of a cardiologist who prescribes finerenone to patients who have comorbid CKD and T2D.
BACKGROUND AND PURPOSE: The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collecti...BACKGROUND AND PURPOSE: The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB). This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration. The efficacy of the compounds was assessed in rodent models of diet induced obesity and diabetes. EXPERIMENTAL APPROACH: In this study, we employed a rational-design approach along with structure-based modeling to develop small-molecule CB1R antagonists that are peripherally acting. Pharmacological profiles of two racemic compounds PB19A and PB95 were evaluated in cannabinoid receptor binding studies, and functional [S]-GTPγS assays. Further chiral separation of enantiomers allowed for the evaluation of respective eutomers in in vitro ADME studies along with in vivo pharmacokinetic and tissue distribution studies in mice. The results showed that the compounds are orally bioavailable and had negligible brain penetrance. The design features also incorporated putative amidine moieties which inhibit the pro-inflammatory enzyme; inducible nitric oxide synthase (iNOS). Both biochemical and in vitro cell-based assays showed the CB1R antagonists having iNOS inhibitor properties. In vivo CB1R functional antagonism was assessed by upper gastrointestinal motility assay. The efficacy of our CB1R antagonists was compared with brain penetrant ibipinabant in a diet-induced obesity mouse model, assessing effects on lipid metabolism biomarkers, food intake, body weight reduction, glucose tolerance and insulin resistance. KEY RESULTS: Novel compounds PB19AE2 and PB95E2 were designed and evaluated as peripherally restricted CB1R antagonists. In high fat diet fed mice, these compounds improved metabolic parameters, modestly reduced food intake, and ameliorated hepatic lipid metabolism markers. CONCLUSION AND IMPLICATIONS: Overall, PB19AE2 and PB95E2 are orally bioavailable, peripherally acting CB1 antagonists and their preliminary evaluation show promising potential in utilizing the pyridazine-based compounds for generating potent leads for treating obesity- associated disorders.
AIMS: To investigate the relationship between glucose-lowering medications and cardio-renal-liver-metabolic (CRLM) health. METHODS: Two-sample Mendelian randomization (MR) was applied to assess the causal relationships b...AIMS: To investigate the relationship between glucose-lowering medications and cardio-renal-liver-metabolic (CRLM) health. METHODS: Two-sample Mendelian randomization (MR) was applied to assess the causal relationships between seven classes of glucose-lowering drugs and CRLM health outcomes. Genetic proxies for drug exposure were identified as cis-acting single nucleotide polymorphisms in the drug target genes, linked to both gene expression levels and glycosylated hemoglobin (HbA1c) or body mass index (BMI). Validation included colocalization and linkage disequilibrium analyses. A two-step MR strategy was employed to explore potential metabolite mediators. RESULTS: Sulfonylureas were associated with a reduced heart failure (HF) risk (odds ratio [OR] = 0.38 per standard deviation change in glucose-lowering drug target perturbation equivalent to 1 unit of HbA1c lowering, P = 2.46E-04) but increased aspartate aminotransferase levels (OR = 1.39, P = 9.50E-07). Sodium-glucose cotransporter-2 inhibitors reduced the risk of acute myocardial infarction (AMI) (OR = 0.37, P = 1.36E-05), venous thromboembolism (VTE) (OR = 0.48, P = 1.89E-04), microalbuminuria (MA) (OR = 0.49, P = 1.65E-06), and increased estimated glomerular filtration rate (eGFR) (OR = 1.04, P = 2.98E-05). They also showed a potential protective effect against general liver disorders (OR = 0.41, P = 4.79E-04), metabolic dysfunction-associated steatotic liver disease (MASLD) (OR = 0.25, P = 0.008), and metabolic syndrome (MetS) (OR = 0.63, P = 5.40E-04). Thiazolidinediones (TZDs) reduced the risk of AMI (OR = 0.44, P = 4.31E-38), hypertension (HT) (OR = 0.60, P = 1.40E-43), MASLD (OR = 0.53, P = 5.61E-05), and MetS (OR = 0.66, P = 1.00E-20) but increased the risk of VTE (OR = 1.40, P = 2.53E-07), atrial fibrillation (OR = 1.61, P = 1.43E-09), and alcoholic liver disease (OR = 3.00, P = 6.56E-11). TZDs also negatively affected eGFR (OR = 0.97, P = 4.68E-05) and increased blood urea nitrogen levels (OR = 1.03, P = 2.52E-09). Glucagon-like peptide-1 receptor agonists demonstrated significant benefits for chronic kidney disease, driven by reductions in both glucose levels (OR = 0.11, P = 0.016) and BMI (OR = 0.20, P = 0.012), with potential cardiometabolic benefits from BMI reduction. Some mediating roles of metabolites have been identified (e.g., SGLT2 inhibitors mediate effects on MA via isoleucine and TZDs mediate effects on MASLD through lipid metabolites). CONCLUSIONS: Glucose-lowering medications exert significant and heterogeneous effects on CRLM health, highlighting the need for personalized treatments and further investigations into their mechanisms and long-term impacts on CRLM outcomes.
BACKGROUND: It has been suggested that dietary factors correlated with red meat may contribute to its adverse health effects, while consuming red meat within a healthy diet may not necessarily increase disease risk. METH...BACKGROUND: It has been suggested that dietary factors correlated with red meat may contribute to its adverse health effects, while consuming red meat within a healthy diet may not necessarily increase disease risk. METHODS: Among 204,740 participants from three prospective cohorts, we examined the association between red meat consumption and risk of type 2 diabetes (T2D) across different levels of diet quality, measured by Alternative Healthy Eating Index (AHEI)-2010 (excluding red and processed meat component), using multivariable-adjusted Cox proportional hazards models. Dietary intake was assessed using repeated food frequency questionnaires. RESULTS: During a median follow-up of 28 years, 18,868 cases were documented. Mean values were 47.3 (SD 8.5) for AHEI-2010 and 6.5 (SD 3.5), 1.8 (SD 1.5), and 4.8 (SD 2.5) servings/week for total, processed, and unprocessed red meat, respectively. Greater red meat consumption was consistently associated with a higher T2D risk across AHEI-2010 strata. Comparing the highest with the lowest quintile of red meat consumption in the highest diet quality quintile, the multivariable-adjusted HRs were 1.95 (1.72, 2.21) for total, 1.88 (1.67, 2.13) for processed, and 1.67 (1.47, 1.90) for unprocessed red meat. Substituting red meat with major food groups was associated with a lower T2D risk, particularly among those with high diet quality. The benefit of lowering red meat consumption was greater in participants with higher diet quality. CONCLUSIONS: The risk associated with high red meat consumption persisted even among participants with a relatively high diet quality, underscoring the importance of limiting red meat consumption to prevent T2D.
BACKGROUND: Protein oxidation (PROTOX) typically accounts for the smallest fraction of daily energy expenditure (24hEE) in humans compared to carbohydrate and lipid oxidation. However, inter-individual differences in PRO...BACKGROUND: Protein oxidation (PROTOX) typically accounts for the smallest fraction of daily energy expenditure (24hEE) in humans compared to carbohydrate and lipid oxidation. However, inter-individual differences in PROTOX may explain differences in fuel partitioning and body weight change. We aimed to elucidate the physiological determinants of PROTOX under controlled 24-h dietary conditions, including eucaloric feeding, fasting, and overfeeding diets with variable protein content. METHODS: Eighty-six weight-stable healthy volunteers with normal glucose regulation (67 M/19F; age: 37 ± 10 years; BMI: 26.7 ± 4.5 kg/m, body fat by DXA: 29.0 ± 9.8 %) underwent 24hEE measurements by whole-room calorimetry during energy balance (20 % protein, 50 % carbohydrate), different overfeeding diets (200 % of the daily eucaloric requirement), including three normal-protein (20 %) diets (balanced: 50 % carbohydrate; high-carbohydrate: 75 % carbohydrate; high-fat: 60 % fat), low-protein (3 %) and high-protein (30 %), and 24-h fasting in a randomized crossover design. Urine samples were collected during each 24-h dietary intervention for quantification of PROTOX and catecholamine excretion rates by nitrogen excretion and high-performance liquid chromatography, respectively. RESULTS: PROTOX during energy balance (mean ± SD: 372 ± 78 kcal/day) was positively associated with protein intake (r = 0.39, p < 0.001), fat free mass (r = 0.35, p < 0.001), but not with fat mass (p = 0.24). Higher PROTOX was associated with higher 24-h urinary norepinephrine (partial r = 0.27, p = 0.01), but not epinephrine (p = 0.48), excretion rates. During normal-protein diets, higher PROTOX was associated with lower lipid oxidation, but showed no association with carbohydrate oxidation. Inter-individual variability in PROTOX did not predict changes in weight or body composition over two years. CONCLUSION: Dietary protein content, lean body mass, and sympathetic nervous system activity are key determinants of PROTOX. Although PROTOX did not predict free-living weight gain, increased PROTOX is associated with decreased lipid oxidation, underscoring its role in fuel partitioning and whole-body energy and substrate balance.
BACKGROUND: We previously reported significant correlations between a direct measure of insulin sensitivity (IS) and blood levels of proteins measured using the Proximity Extension Assay (PEA) in two European cohorts. Ho...BACKGROUND: We previously reported significant correlations between a direct measure of insulin sensitivity (IS) and blood levels of proteins measured using the Proximity Extension Assay (PEA) in two European cohorts. However, protein correlations with IS within non-European populations, in response to short-term interventions that improve IS, and any causal associations with IS have not yet been established. METHODS: We measured 1470 proteins using the PEA in the plasma of 1015 research participants at Stanford University who underwent one or more direct measures of IS. Association analyses were carried out with multivariable linear regression within and across Stanford subgroups and within each of the two European cohorts. Association statistics were also meta-analyzed after transformation and harmonization of the two direct measures of IS. Lastly, we performed genome-wide association studies of IS and used genetic instruments of plasma proteins from the UK Biobank to identify candidate causal proteins for IS through Mendelian Randomization (MR) analysis. RESULTS: In age and sex adjusted model, 810 proteins were associated with baseline IS among 652 self-reported European participants in the Stanford cohort at a false discovery rate (FDR) < 0.05. Effect sizes for these proteins were highly correlated with those observed in 122 South Asian, 92 East Asian, 85 Hispanic, and 52 Black/African American persons (r = 0.68 to 0.83, all P ≤ 4.3 × 10). Meta-analysis of the full Stanford cohort with the two European cohorts (N = 2945) yielded 247 significant protein associations (FDR < 0.05), with 50 remaining significant after further adjustment for body mass index. In a subset of Stanford participants undergoing insulin sensitizing interventions (N = 53 taking thiazolidinediones, N = 66 with weight loss), 79.3 % of protein level changes were directionally consistent with the respective baseline association (observed/expected p = 6.0 × 10). MR analyses identified ten candidate causal proteins for IS, among which were SELE and ASGR1, proteins with established drug targets currently under investigation. CONCLUSION: Plasma proteins measured using the PEA provide a robust signature for IS across diverse populations and after short-term insulin sensitizing interventions highlighting their potential value as universal biomarkers of insulin resistance. A small subset of markers provided insights into potential causal molecular mechanisms and therapeutic targets.
AIM: Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomy...AIM: Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes homeostasis. This study aimed to elucidate the roles and mechanisms of UBC9 in DCM development. METHODS: We established cardiomyocyte-specific UBC9 knockout mice and UBC9-overexpressing mice in vivo. A DCM model was established by feeding a high-fat diet and administering a low-dose streptozotocin injection. Proteomics, H&E staining, Sirius Red staining, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis, hypertrophy, and mitophagy in the myocardium. Neonatal mouse cardiomyocytes (NMCMs) were cultured in vitro and stimulated with palmitic acid, UBC9 overexpression adenovirus, and small interfering RNA to establish UBC9 overexpression or knockdown NMCMs. Real-time PCR, western blotting, and immunoprecipitation were employed to examine the roles and mechanisms of UBC9 in cardiomyocyte mitophagy. RESULTS: The transcription and protein levels of UBC9 were significantly decreased in the myocardium of DCM mice. Cardiomyocyte-specific UBC9 knockout aggravated cardiac dysfunction, myocardial fibrosis, hypertrophy, and impaired mitophagy. Conversely, UBC9 overexpression produced opposite effects. UBC9 protected cardiomyocyte mitophagy independently of SUMOylation. UBC9 exerted protective effects against defective cardiomyocyte mitophagy by directly binding to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increased PSEN2 expression. Moreover, the impact of UBC9 on cardiomyocyte mitophagy was reversed upon PSEN2 knockdown. CONCLUSIONS: UBC9 alleviated DCM development through the NEDD4/RUNX2/PSEN2 pathway. These findings offer novel insights into the potential of UBC9 as a therapeutic target for DCM.
Beghini M, Metz M, Baumgartner C
… +31 more, Wolf P, Bastian M, Hackl M, Baumgartner-Parzer S, Marculescu R, Krebs M, Harreiter J, Brandt S, Miehle K, Ceccarini G, Magno S, Pelosini C, Tran C, Gambineri A, Cecchetti C, Gard LI, Risti R, Lõokene A, Krššák M, Pfleger L, Trauner M, Kautzky-Willer A, Stumvoll M, Wabitsch M, Santini F, Turan I, Akinci B, Frommlet F, Stangl H, Fürnsinn C, Scherer T
BACKGROUND AND AIMS: Metreleptin ameliorates hepatic steatosis partially independent of its anorexic action. We previously showed that metreleptin increases hepatic very low-density lipoprotein triglycerides (VLDL1-TG) e...BACKGROUND AND AIMS: Metreleptin ameliorates hepatic steatosis partially independent of its anorexic action. We previously showed that metreleptin increases hepatic very low-density lipoprotein triglycerides (VLDL1-TG) export in rodents and healthy humans requiring intact hepatic autonomic innervation. The primary aim of this study was to investigate whether metreleptin has anti-steatotic properties in patients with lipodystrophy by increasing VLDL1-TG export. In addition, we present a case of generalized lipodystrophy undergoing metreleptin treatment after liver transplantation, a model for hepatic autonomic denervation. METHODS: In this randomized, placebo-controlled, crossover trial (EudraCT 2017-003014-22) we assessed the acute effects of a single metreleptin injection in 10 patients (8 females, 2 males; mean age ± SD: 49 ± 14 yrs; 9 familial partial and 1 generalized lipodystrophy) on hepatic VLDL1-TG secretion and hepatocellular lipid content (HCL) measured via an intravenous fat emulsion test and H-magnetic resonance spectroscopy, respectively. RESULTS: We found that a single injection of metreleptin increased hepatic VLDL1-TG secretion by 75 % (mean difference ± SD: +219 ± 149 mg/h metreleptin vs. placebo; p = 0.001), without significant changes in HCL within 3 h (mean difference ± SD: -8 ± 14 % metreleptin vs. placebo, p = 0.14). Metreleptin therapy in a patient with generalized lipodystrophy following liver transplantation failed to ameliorate hepatic steatosis despite improving glucose and lipid metabolism. CONCLUSIONS: Leptin acutely increases hepatic VLDL1-TG secretion in patients with lipodystrophy, likely contributing to metreleptin's body weight-independent anti-steatotic effects. The case report suggests that intact autonomic liver innervation may be required for this action, warranting further research.
BACKGROUND: Insulin-induced lipohypertrophy (ILH) is the most frequent injection site side effect of insulin therapy. ILH consists of local adipose tissue overgrowth at the insulin injection site that eventually progress...BACKGROUND: Insulin-induced lipohypertrophy (ILH) is the most frequent injection site side effect of insulin therapy. ILH consists of local adipose tissue overgrowth at the insulin injection site that eventually progresses to lipoma-like masses of a relatively large size, causing discomfort and disfiguration. Insulin injection into ILH areas delays insulin delivery, and the presence of ILH is associated with poor glycemic control and more frequent hypoglycemic events. Although, in principle, the development of ILH can be minimized by avoiding injecting insulin in the same spot, in practice, ILH remains highly prevalent. So far, no molecular mechanism for ILH has been proposed. METHODS: We screened a panel of PI3K inhibitors with different specificities for their capacity to reduce insulin signaling and growth of human primary adipocytes exposed to pharmacological doses of insulin. The two most effective inhibitors from the screening above were investigated in an in-vivo model of ILH. RESULTS: We identified PI3K inhibitors capable of reducing the hypertrophic (enlargement of lipid droplets) and hyperplastic (adipocyte differentiation) growth of primary human adipocytes exposed to pharmacological doses of insulin. Since preventing ILH development requires only a localized inhibition of PI3K activity, using a low dose of high-affinity PI3K inhibitors, we could prevent the development of ILH in a mouse model without inhibiting the systemic effects of insulin on blood glucose and without causing any apparent adverse reaction. CONCLUSION: We now show evidence indicating that ILH is caused by pathological PI3K activation at insulin injection sites and that ILH can be prevented by local inhibition of PI3K activity at the injection site.
BACKGROUND: The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear. METHODS: In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined cli...BACKGROUND: The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear. METHODS: In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined clinical and experimental aspects to investigate the effects and mechanisms of eldecalcitol, an active form of vitamin D, in preventing sarcopenia. We examined changes in molecules involved in muscle synthesis and degradation pathways in muscle samples from 32 participants before and after 1 year of eldecalcitol or placebo treatment. The protein levels of molecules involved in muscle synthesis and degradation pathways were examined using western blotting. Additionally, the skeletal muscle and body fat volumes were measured using bioelectrical impedance analysis with a body composition analyzer. RESULTS: We found that eldecalcitol treatment for 1 year resulted in higher phosphorylation levels of mTOR and FOXO1 signaling pathways, which are associated with increased muscle mass and strength than those with placebo treatment. Body composition measurements at 1 year showed that the eldecalcitol group had significantly higher skeletal muscle mass (1.9 % vs. -3.4 %, p = 3.26E-9) and muscle strength (4.1 % vs. -0.7 %, p = 2.57E-17), and lower fat mass (-3.2 % vs. 1.8 %, p = 1.73E-12) than those in the placebo group. CONCLUSION: This study suggested that the active form of vitamin D regulates the protein synthesis and degradation pathways in human skeletal muscle and may help prevent sarcopenia. This study was registered at UMIN clinical trials registry, UMIN 000005394.
Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant...Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific signatures in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data. We performed a systematic review and individual transcriptomic analysis of eight selected studies which included 302 subcutaneous adipose tissue samples. Then, we conducted different gene-level meta-analyses and functional characterizations for obesity and T2D separately, identifying common and sex-specific transcriptional profiles, many of which were previously associated with obesity or T2D. The obesity meta-analysis yielded nineteen differentially-expressed genes from a sex-specific perspective (e.g., SPATA18, KREMEN1, NPY4R, and PRM3), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (SAMD9, NBPF3, LDHD, and EHD3) and females (RETN, HEY1, PLPP2, and PM20D2). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females, and the roles of mitochondrial damage and free fatty acids in males. Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and further T2D development, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.
Ribas-Latre A, Hoffmann A, Gebhardt C
… +18 more, Weiner J, Arndt L, Raulien N, Gericke M, Ghosh A, Krause K, Klöting N, Pfluger PT, Sheikh BN, Ebert T, Tönjes A, Stumvoll M, Wolfrum C, Blüher M, Wagner U, Vendrell J, Fernández-Veledo S, Heiker JT
Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue t...Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.
Fernández-Duval G, Razquin C, Wang F
… +25 more, Yun H, Hu J, Guasch-Ferré M, Rexrode K, Balasubramanian R, García-Gavilán J, Ruiz-Canela M, Clish CB, Corella D, Gómez-Gracia E, Fiol M, Estruch R, Lapetra J, Fitó M, Serra-Majem L, Ros E, Liang L, Dennis C, Asensio EM, Castañer O, Planes FJ, Salas-Salvadó J, Hu FB, Toledo E, Martínez-González MA
Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseli...Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality. The multi-metabolite signature created as a linear combination of these selected metabolites, also showed a strong association with all-cause mortality using plasma samples collected at 1-year follow-up in PREDIMED. This association was subsequently confirmed in 4 independent American cohorts, validating the signature as a consistent predictor of all-cause mortality across diverse populations.
Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallma...Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.