Levels Of Growth Differentiation Factor Research Articles

Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study

Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima–media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60–69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.

Effect of Acute Nutritional Ketosis on Circulating Levels of Growth Differentiation Factor 15: Findings from a Cross-Over Randomised Controlled Trial.

Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether growth differentiation factor 15 (GDF-15)-an anorexigenic hormone-is involved in this process. The aim was to investigate the effect of a ketone ester beverage delivering β-hydroxybutyrate (KEβHB) on plasma levels of GDF-15, as well as assess the influence of eating behaviour on it. The study was a randomised controlled trial (registered at clinicaltrials.gov as NCT03889210). Individuals were given a KEβHB beverage or placebo in a cross-over fashion. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 min after ingestion. Eating behaviour was assessed using the three-factor eating questionnaire. GDF-15 levels were not significantly different (p = 0.503) after the KEβHB beverage compared with the placebo. This finding remained consistent across the cognitive restraint, emotional eating, and uncontrolled eating domains. Changes in the anorexigenic hormone GDF-15, irrespective of eating behaviour, do not appear to play a major role in the glucose-lowering effect of exogenous ketones.

Growth Differentiation Factor-15 Is Considered a Predictive Biomarker of Long COVID in Non-hospitalized Patients.

Mitochondrial dysfunction is associated with various diseases. Mitochondria plays a regulatory role during infection. The association between mitokines and subsequent COVID progression has not been previously studied. The retrospective cohort study aimed to investigate the potential of serum mitokines as long COVIDbiomarkers in non-hospitalized patients. Patients with confirmed SARS-CoV-2 infection and blood test reports between January 2021 and April 2023 were included. Patients were categorized into two groups, the recovered and long COVID groups, based on fatigue, decline in focus, and pain. Serum levels of growth differentiation factor 15 (GDF-15) and fibroblast growth factor-21 (FGF-21), which are affected by mitochondrial function, along with inflammatory and vascular endothelium markers, were measured using enzyme-linked immunosorbent assays (ELISA). A receiver operating characteristic curve was used to screen the biomarkers. The threshold value of GDF-15 in the acute phase was 965 pg/mL (sensitivity: 71.4%, specificity: 83.3%), indicating that GDF-15 may be associated with the presence of symptoms three months post onset. No association with inflammatory markers and vascular structures was observed. Therefore, elevated GDF-15 levels in the acute phase may act as a predictive biomarker of long COVID.

Serum Levels of Growth Differentiation Factor 15 as a Biomarker for Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Background: Growth Differentiation Factor 15 (GDF-15) has been identified as a biomarker of cellular stress conditions and has demonstrated functional implications in kidney disease, metabolic disorders, and diabetes. However, the relationship between GDF-15 and the coexistence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remains unclear. This study aims to investigate the association between GDF-15 levels and the presence of CKD in patients with T2DM, then analyze the cut off value. Method: A cross-sectional study was conducted, enrolling a total of 60 patients. T2DM patients were categorized into two groups based on the presence or absence of CKD. Serum GDF-15 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Results: The study population (n=60) predominantly consisted of male individuals with an average age of 53 years. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.846 (95% CI = 0.748 – 0.945) with a statistically significant p-value of < 0.001. The optimal cut-off value for serum GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL, with corresponding sensitivity and specificity values of 77% and 79%, respectively. Furthermore, a significant association between GDF-15 levels and both T2DM without CKD and T2DM with CKD was observed (p < 0.001). Conclusion: There is a significant association observed between serum GDF-15 levels in patients with type 2 diabetes mellitus (DM) and the presence of CKD. The cut of value GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL with sensitivity and specificity values of 77% and 79%, this is can be considered as a potential biomarker for the detection of CKD in individuals with T2DM.

Abstract 5861: CDK4/6 therapy-induced senescence as a resistance mechanism-MiDAS touch

Abstract Background: Cyclin-dependent kinase inhibitors (CDK4/6i) have revolutionized the therapy for estrogen receptor positive (ER+) breast cancer. Despite the response to CDK4/6i, resistance and recurrence are still a clinical reality, resulting in death due to breast cancer. G1 cell cycle arrest has been considered as the main mechanism of action of CDK4/6i in luminal breast cancer. However, the response to therapy does not correlate with the expression of CDK4/6 or key cell cycle proteins. It is also unclear whether CDK4/6i-induced senescence enhances the therapeutic response or mediates development of resistance. Experimental Procedures: We have developed drug-tolerant persisters resistant to CDK4/6 inhibitors (CDK4/6i-DTPs) in a panel of estrogen receptor positive (ER+) cells to explore the molecular mechanisms associated with resistance. Using different cell phenotype assays (i.e., cell viability/cell cycle, senescence/senescence reversibility and wound healing) as well as senescence-associated secretory phenotype (SASP) human cytokine array of 105 markers, we characterized the phenotype and secretome of these CDK4/6i DTPs. Summary: CDK4/6i-DTPs induced by abemaciclib, palbociclib and ribociclib (all from Selleckchem) demonstrated resistance to these drugs and dramatically slowed growth. The percentage of senescent cells reached 30-89% of the total population for all cell lines in all three drugs, whereas control parental cells exhibited around 10%. CDK4/6i DTPs also exhibited significant cell migration, and increased lysosomal phenotype compared to their parental sensitive cells. Further analysis with human cytokine array revealed that protein levels of growth differentiation factor 15 (GDF-15) are elevated in both cell lysates and conditioned-media of CDK4/6i DTPs, whereas Serpin E1 (Plasminogen Activator Inhibitor, Type I, PAI-1) was unique to secreted CDK4/6i DTPs. Interestingly, we did not observe changes in pro-inflammatory senescence-associated secretory phenotype (SASP) markers such as interleukins. Apart from being a SASP protein, GDF-15 is a mitochondrial cytokine (mitokine), suggesting a role in mitochondrial dysfunction-associated senescence (MiDAS). HMGB1, and LMNB1 are also down-regulated in CDK4/6-DTPs supporting the MiDAS phenotype. CDK4/6i-induced MiDAS appears to be transient, as CDK4/6i-DTPs reverted to the parental phenotype in drug-free culture media 20 days after the removal of CDK4/6i's. This included growth characteristics and sensitivity to CDK4/6i. This reversion of phenotype was observed in all five cell line models tested with all three drugs. Conclusions: CDK4/6-induces a mitochondrial dysfunction-associated senescence (MiDAS). This appears to be transient in nature as withdrawal of the drug results reacquisition of parental cell phenotype and drug-sensitivity. Targeting MiDAS pathway might be critical to improve efficacy of CDK4/6 inhibitors. Citation Format: Yesim Gokmen-Polar, Yuan Gu, Ling Ruan, Sunil S. Badve. CDK4/6 therapy-induced senescence as a resistance mechanism-MiDAS touch [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5861.

GDF15 Contributes to the Regulation of the Mechanosensitive Responses of PdL Fibroblasts through the Modulation of IL-37.

During orthodontic tooth movement (OTM), areas of compressive and tensile forces are generated in the periodontal ligament (PdL), a mechanoreactive connective tissue between the teeth and alveolar bone. Mechanically stimulated PdL fibroblasts (PdLFs), the main cell type of PdL, express significantly increased levels of growth differentiation factor 15 (GDF15). In compressed PdL areas, GDF15 plays a fundamental role in modulating relevant OTM processes, including inflammation and osteoclast activation. However, the specific function of this factor in tensile areas has not yet been investigated. Thus, the aim of this study was to investigate the role of GDF15 in the mechanoresponse of human PdLFs (hPdLFs) that were exposed to biaxial tensile forces in vitro. Using siRNA-mediated knockdown experiments, we demonstrated that GDF15 had no impact on the anti-inflammatory force response of elongated hPdLFs. Although the anti-inflammatory markers IL1RN and IL10, as well as the activation of immune cells remained unaffected, we demonstrated an inhibitory role of GDF15 for the IL-37 expression. By analyzing osteogenic markers, including ALPL and RUNX2, along with an assessment of alkaline phosphatase activation, we further showed that the regulation of IL-37 by GDF15 modulates the osteogenic differentiation potential of hPdLFs. Despite bone resorption in tensile areas being rather limited, GDF15 was also found to positively modulate osteoclast activation in those areas, potentially by adjusting the IL-37 levels. In light of our new findings, we hypothesize that GDF15 modulates force-induced processes in tissue and bone remodeling through its various intra- and extracellular signaling pathways as well as interaction partners. Potentially acting as a master regulator, the modulation of GDF15 levels may hold relevance for clinical implications.

Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Reduced plasma GDF10 levels are positively associated with cholesterol impairment and childhood obesity

Childhood obesity is a global health concern affecting over 150 million children worldwide, with projections of a rise to 206 million by 2025. Understanding the mechanisms underlying this epidemic is crucial for developing effective interventions. In this study, we investigated circulating levels of Growth Differentiation Factor 10 (GDF10), a novel regulator of adipogenesis. Previous studies report diminished circulating GDF10 levels contribute to obesity and hepatic steatosis in mice. To further understand the role of plasma GDF10 in childhood obesity, a prospective case–control study was conducted. Using an enzyme-linked immunosorbent assay, plasma GDF10 levels were measured in children aged 5–17 years of age with normal (n = 36) and increased (n = 56) body mass index (BMI). Subsequently, plasma GDF10 levels were compared to various cardio-metabolic parameters. Children with increased BMI exhibit significantly lower levels of plasma GDF10 compared to children with normal BMI (p < 0.05). This study not only supports previous mouse data but is the first to report that lower levels of GDF10 is associated with childhood obesity, providing an important human connection for the relevance of GDF10 in obesity. Furthermore, this study revealed a significant correlation between low plasma GDF10 levels and elevated LDL-cholesterol and total cholesterol levels dependent on BMI (95% CI, p < 0.05). This study supports the hypothesis that children with obesity display lower plasma levels of GDF10, which correlates with elevated cholesterol levels. These insights shed light on potential mechanisms contributing to childhood obesity and may lead to future therapeutic interventions targeting GDF10 to mitigate adverse effects of adipogenesis in cardiometabolic health.

The correlation between serum growth differentiation factor 15 and malnutrition in patients with end-stage kidney disease on hemodialysis

Objective Malnutrition commonly occurs in patients undergoing maintenance hemodialysis. Early detection of malnutrition could allow early interventions to prevent later complications. At present, there are not many biomarkers with high predictive value of end-stage kidney disease (ESKD)-related malnutrition, especially for early malnutrition in hemodialysis patients, which needs more in-depth research. Therefore, we performed a cross-sectional study on 97 patients to identify biomarkers for malnutrition in hemodialysis patients. Research Methods & Procedures 7-point subjective global assessment (SGA) was applied to evaluate the nutritional status of patients on hemodialysis. Serum levels of growth differentiation factor 15 (GDF15), albumin, pre-albumin, c-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), hemoglobin, low density lipoprotein-cholesterol, and high density lipoprotein-cholesterol were detected before hemodialysis. Logistic analysis and linear regression were used to analyze the association between GDF15 levels and the SGA score after adjustment for basic characteristics and laboratory findings. Results Among the 97 patients on hemodialysis, 51 had malnutrition (SGA < 6). There was no difference between the malnourished and well nourished (SGA ≥ 6) groups for dialysis duration, cholesterol, CRP, TNF-α, and hemoglobin. The malnutrition group had significantly lower grip strength (p < 0.05). GDF15 levels correlated negatively with the SGA score after adjustment for possible confounding factors [rho (male) = -0.312, rho(female)= -0.437;P(male) = 0.0181, P(female) = 0.005], and might contribute to the malnutritional status, the AUCs of GDF15 for malnutrition was 0.697 (p = 0.011) in male and 0.828 (p < 0.001) in female. Conclusions GDF15 is associated with malnutrition according to the SGA score in patients with ESKD on hemodialysis, suggesting that GDF15 might be involved in the pathogenesis of malnutrition patients with ESKD in this setting. Furthermore, GDF15 is likely to be a potential diagnostic biomarker for malnutrition according to the SGA score.

GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.

We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.

Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10-5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; pprefrailty = 1 × 10-15 , pfrailty = 2 × 10-19 ), transgelin (TAGLN; pprefrailty = 2 × 10-12 , pfrailty = 6 × 10-22 ), and insulin-like growth factor-binding protein 2 (IGFBP2; pprefrailty = 5 × 10-15 , pfrailty = 1 × 10-15 ) and with a lower level of growth hormone receptor (GHR, pprefrailty = 3 × 10-16 , pfrailty = 2 × 10-18 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10-5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma.

Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease. Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot. Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls. The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.

Systemic GDF11 replenishment ignites myocardial injury through diminishing anti-apoptotic activity of cardiac progenitor cells

Abstract Background Tissue damage due to acute myocardial infarction is caused by both the ischemic insult and subsequent reperfusion injury (I/R). Restoration of coronary blood flow accelerates cardiomyocyte death, a phenomenon referred to as reperfusion injury, the extent of which is partly modulated by cardiac progenitor cells (CPC). Development of novel therapies to reduce infarct size, the main determinant of outcome, represent a huge unmet medical need (1). Systemic levels of growth differentiation factor 11 (GDF11), a TGF-β superfamily member that shares 90% homology with myostatin, decline with age, and GDF11 replenishment by heterochronic parabiosis or systemic recombinant GDF11 (rGDF11) delivery was postulated to have rejuvenating effects (2). Purpose We aimed to probe the effects of systemic GDF11 replenishment on I/R injury and deepen insights into the molecular mechanisms involved. Methods We designed a vehicle-controlled study in which young (3–4 months) and old (22–24 months) C57Bl/6 mice were randomly assigned to either daily systemic rGDF11 or control treatment over 30 days before myocardial I/R injury was induced. Dissected hearts were subjected to in-depth profiling followed by IPA-guided -omics to identify key regulatory mechanisms. Finally, in vitro experiments on human CPCs and HL-1 cardiomyocytes were performed. Results Myocardial Gdf11 expression declined with age, whereas myostatin (Mstn) showed an opposing expression pattern (Fig. 1A), a trend similarly observed upon I/R (Fig. 1B). Surprisingly, after the 30-day study period (Fig. 1C), young and aged rGDF11-treated mice showed higher I/R-induced infarct size and serum cardiac troponin I levels than controls, despite comparable areas at risk (Fig. 1D). Importantly, while proxies of necroptosis/pyroptosis remained unchanged, rGDF11-treated animals showed reduced cardiomyocyte viability irrespective of their age (Fig. 2A). Targeted transcriptomics applied on cardiac tissues of both groups identified the CPC-marker Nkx2–5 to be differentially regulated (Fig. 2B-C), an expression pattern validated in an independent cohort at both mRNA and protein levels (Fig. 2D). In the adult myocardium, the expression of both Nkx2–5 and its cofactor Gata4 is mainly confined to CPCs; indeed, similar reductions in Nkx2–5 and Gata4 expression were observed in CPCs exposed to rGDF11 (Fig. 2E) which coincided with accelerated cardiomyocyte death if cultured in conditioned media obtained from CPCs treated with rGDF11 (Fig. 2F), pointing toward a paracrine signalling pathway. Conclusions Myocardial expression of GDF11 declines with age, and is blunted upon I/R injury, thereby opposing the expression pattern of myostatin. Surprisingly, however, systemic GDF11 replenishment by rGDF11 supplementation enhances rather than reduces myocardial infarct size through augmented apoptosis, a phenomenon mediated by diminished cardioprotective function of CPCs. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Foundation for Cardiovascular Research – Zurich Heart House

Levels of Growth Differentiation Factor 15 and Interleukin-29 in Children and Adolescents with Type 1 Diabetes Mellitus

Levels of Growth Differentiation Factor 15 and Interleukin-29 in Children and Adolescents with Type 1 Diabetes Mellitus

Abstract 2418: Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma

Abstract The most recent advance in the treatment of osteosarcoma (OS) occurred in the 1980s when multi-agent chemotherapy was shown to improve overall survival compared to surgery alone. Animal model investigations can accelerate the understanding of human diseases and since few models are available for OS, we refined a rat model to ask questions regarding pathways of metastasis and metastasis biomarker predictiveness. The outbred Sprague-Dawley (SD) rat model is an immunocompetent, syngeneic model, as we implant UMR106 OS cells (ATCC), which were originally isolated from a SD OS. We developed a reproducible method to orthotopically implant cells into the tibia microenvironment and to amputate the limb for longitudinal studies. Using young rats, we also modeled pediatric OS. We found that rats develop reproducible primary and metastatic pulmonary tumors which histologically resemble human primary and metastatic osteosarcoma. Using immunohistochemistry methods, we found that primary OS is infiltrated with numerous macrophages with relatively fewer CD3+ T cells. A protein expression survey of these OS cells revealed significant expression of ErbB family receptor tyrosine kinases (ErbB2, ErbB4), which have recently been shown to be anti-inflammatory against macrophages. We also discovered that rats with osteosarcoma have markedly high serum levels of Growth Differentiation Factor 15 (GDF15), also called Macrophage Inhibitory Cytokine 1, a member of the TGF beta family of proteins, which is also frequently expressed with ErbB2 in cancers. GDF15 was measured by ELISA. Western blot analysis showed that GDF15 precursor (pro-peptide) was expressed in primary and metastases. This model will enable studies with anti-ErbB2 or GDF15 pathway inhibition to assess the role of macrophage activation in the setting of pathway inhibition and chemotherapy, as well as how pathway inhibition modulates metastasis incidence. In vivo and invitro, systems will enable the assessment of the role of GDF15 as a potential biomarker of metastasis, compared to tibial radiographic patterns, serum alkaline phosphatase, and lung histopathology. In conclusion, we have an immunocompetent, syngeneic orthotopic osteosarcoma rat model which affectively resembles human osteosarcoma, and can be used for better understanding metastasis mechanisms and metastasis biomarkers. Citation Format: Shun Ishiyama, Bailey West, Hyo-Jeong Han, Xin Guo, Tomoaki Ito, Harumi Saeki, Malcolm V. Brock, Kathleen Gabrielson. Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2418.

Camptothecin effectively treats obesity in mice through GDF15 induction.

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

Increased Circulating Levels of Growth Differentiation Factor 15 in Association with Metabolic Disorders in People Living with HIV Receiving Combined Antiretroviral Therapy.

Objective: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS). Atherosclerosis and inflammation are related to growth differentiation factor-15 (GDF15). The relationship between metabolic disturbances, HALS, and CVR with GDF15 in PLWH is not known. Research design and methods: Circulating GDF15 levels in 152 PLWH (with HALS = 60, without HALS = 43, cART-naïve = 49) and 34 healthy controls were assessed in a cross-sectional study. Correlations with lipids, glucose homeostasis, fat distribution, and CVR were explored. Results: PLWH had increased circulating GDF15 levels relative to controls. The increase was the largest in cART-treated PLWH. Age, homeostatic model assessment of insulin resistance 1 (HOMA1-IR), HALS, dyslipidemia, C-reactive protein, and CVR estimated with the Framingham score correlated with GDF15 levels. The GDF15-Framingham correlation was lost after age adjustment. No correlation was found between GDF15 and the D:A:D Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) score estimated CVR. CVR independent predictors were patient group (naïve, HALS−, and HALS+) and cumulated protease inhibitor or nucleoside reverse transcriptase inhibitor exposure. Conclusions: PLWH, especially when cART-treated, has increased GDF15 levels—this increase is associated with dyslipidemia, insulin resistance, metabolic syndrome, HALS, and inflammation-related parameters. GDF15 is unassociated with CVR when age-adjusted.

GDF15 Supports the Inflammatory Response of PdL Fibroblasts Stimulated by P. gingivalis LPS and Concurrent Compression.

Periodontitis is characterized by bacterially induced inflammatory destruction of periodontal tissue. This also affects fibroblasts of the human periodontal ligaments (HPdLF), which play a coordinating role in force-induced tissue and alveolar bone remodeling. Excessive inflammation in the oral tissues has been observed with simultaneous stimulation by pathogens and mechanical forces. Recently, elevated levels of growth differentiation factor 15 (GDF15), an immuno-modulatory member of the transforming growth factor (TGFB) superfamily, were detected under periodontitis-like conditions and in force-stressed PdL cells. In view of the pleiotropic effects of GDF15 in various tissues, this study aims to investigate the role of GDF15 in P. gingivalis-related inflammation of HPdLF and its effect on the excessive inflammatory response to concurrent compressive stress. To this end, the expression and secretion of cytokines (IL6, IL8, COX2/PGE2, TNFα) and the activation of THP1 monocytic cells were analyzed in GDF15 siRNA-treated HPdLF stimulated with P. gingivalis lipopolysaccharides alone and in combination with compressive force. GDF15 knockdown significantly reduced cytokine levels and THP1 activation in LPS-stimulated HPdLF, which was less pronounced with additional compressive stress. Overall, our data suggest a pro-inflammatory role for GDF15 in periodontal disease and demonstrate that GDF15 partially modulates the force-induced excessive inflammatory response of PdLF under these conditions.

Association of growth differential factor-15, hs-cardiac troponin T and N-terminal pro-brain natriuretic peptide with coronary artery disease in patients undergoing elective coronary angiography

Abstract Background Although the importance of conventional risk factors is well established, a significant proportion of patients with coronary artery disease (CAD) lack any of these factors and many patients without CAD have one or more of them. Better tools are needed to improve risk stratification of patients. Purpose We aimed to investigate the association between plasma levels of growth differentiation factor 15 (GDF-15), a marker of stress and inflammation, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with the presence of CAD in stable patients referred for elective coronary angiography. Methods Plasma levels of the three biomarkers were measured in 252 consecutive patients. Patients with known CAD, acute coronary syndrome, or with chronic inflammatory conditions were excluded. CAD was defined by the presence of at least one lesion causing &amp;gt;50% stenosis. The outcome was defined as an ordinal variable with 3 levels: no CAD, 1- or 2-vessel CAD and 3-vessel or left main CAD. Results Median age was 63 years (56–71), and 35% of patients were females. Among conventional risk factors, hypertension was the most prevalent (70%), followed by hyperlipidemia (69%), smoking (42%), diabetes (33%) and family history of CAD (32%). Of the 252 patients enrolled, 153 (61%) had no CAD, 81 (32%) 1- or 2-vessel CAD, and 18 (7%) 3-vessel or left main CAD. Plasma levels of GDF-15, hs-cTnT and NT-proBNP in each of the 3 groups of CAD are summarized in table 1. In unadjusted ordinal logistic regression analysis, GDF-15 and hs-cTnT were statistically significantly associated with the presence and extent of CAD, while NT-proBNP was not (table 1). However, in a multivariable analysis including age, sex and traditional risk factors, the association of GDF-15 and hs-cTnT with angiographic CAD was attenuated and no longer statistically significant. Age, male sex, family history of premature CAD and the presence of hyperlipidemia, were independent predictors of the presence and extent of CAD (table 2). Conclusion In stable patients referred for coronary angiography, plasma levels of GDF-15 and hs-cTnT could predict the presence of CAD when evaluated separately. However, that association was attenuated by clinical characteristics. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Roche Diagnostics International LtdForrenstrasse 26343 RotkreuzSwitzerland Table 1Table 2

Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer.

Simple SummaryGrowth differentiation factor 15 (GDF-15) is a stress responsive cytokine that mediates food intake, energy consumption, and body weight. We aimed to evaluate whether circulating GDF-15 level could be associated with cachexia symptoms, which include loss of skeletal muscle mass, systemic inflammatory reaction, poor performance status, anorexia, shortened survival time and biological tumor activity in advanced pancreatic cancer (APC). The cut-off for serum GDF-15 was 3356.6 pg/mL, as the mean plus two standard deviations in patients with benign pancreatic disease. APC patients with high serum GDF-15 showed worsened performance, anorexia and elevations of inflammatory and tumor burden, signatures of cachexia, and activation of Akt and JNK in tumor GDF-15-producing pathways. This study identified tumor-driven GDF-15 as a potential cause of cachexia symptoms in APC.We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC.