Explore the vast range of titles available.

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk 1 , 2 . More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner 3 . The molecular mechanisms by which metformin lowers body weight are unknown. Here we show—in two independent randomized controlled clinical trials—that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent. In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation. The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.

Aims/hypothesisGrowth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI.MethodsWe obtained SNPs strongly (p value <5 × 10−8) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium.ResultsUsing 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer.Conclusions/interpretationThere is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15 . Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels. GDF-15 is a cytokine regulating food intake and a potential therapeutic target for treating obesity. Here, the authors show that macrophage infiltration in adipose tissue increases GDF-15 during obesity and type 2 diabetes, and hepatocyte stress further increases its levels when developing MASH.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2 , ATP13A3 , AQP1 and SOX17 .

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of \"CTD-negative\" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Background Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β (TGF-β) superfamily that has gained considerable attention over the last decade for its observed ability to reverse age-related deterioration of multiple tissues, including the heart. Yet as many researchers have struggled to confirm the cardioprotective and anti-aging effects of GDF11, the topic has grown increasingly controversial, and the field has reached an impasse. We postulated that a clearer understanding of GDF11 could be gained by investigating its health effects at the population level. Methods and results We employed a comprehensive strategy to interrogate results from genome-wide association studies in population Biobanks. Interestingly, phenome-wide association studies (PheWAS) of GDF11 tissue-specific cis -eQTLs revealed associations with asthma, immune function, lung function, and thyroid phenotypes. Furthermore, PheWAS of GDF11 genetic variants confirmed these results, revealing similar associations with asthma, immune function, lung function, and thyroid health. To complement these findings, we mined results from transcriptome-wide association studies, which uncovered associations between predicted tissue-specific GDF11 expression and the same health effects identified from PheWAS analyses. Conclusions In this study, we report novel relationships between GDF11 and disease, namely asthma and hypothyroidism, in contrast to its formerly assumed role as a rejuvenating factor in basic aging and cardiovascular health. We propose that these associations are mediated through the involvement of GDF11 in inflammatory signaling pathways. Taken together, these findings provide new insights into the health effects of GDF11 at the population level and warrant future studies investigating the role of GDF11 in these specific health conditions.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor‐β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro‐angiogenic activities of MSCs, mouse bone marrow–derived MSCs were engineered to overexpress GDF11 (MSCGDF11) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSCGDF11 than control MSCs (MSCVector) during differentiation. More tube formation was observed in MSCGDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSCGDF11 showed more differentiation into CD31+ endothelial‐like cells and better pro‐angiogenic activity as compared with MSCVector. Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular‐signal‐related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF‐β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro‐angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ‐R/ERK/EIF4E pathway.

Background: It has been reported the therapeutic effects of mesenchymal stem cells (MSCs) on hearing loss. This study explored the therapeutic effects of growth differentiation factor 6 (GDF6) overexpression-induced MSCs (MSCs-GDF6) on age-related hearing loss (ARHL) and its underlying mechanisms. Methods: Reverse transcription-quantitative PCR and western blotting were used to evaluate gene expression. Flow cytometry and immunofluorescence assays were performed for the detection of apoptosis and autophagy, respectively. Hearing function and loss of outer hair cells (HCs) in ARHL rats were measured using the auditory brainstem response and cochlear silver nitrate staining, respectively. MSC proliferation was evaluated with the Cell Counting Kit-8 assay. Results: Growth differentiation factor 15 (GDF15) and sirtuin 1 (SIRT1) expression was significantly decreased in hydrogen peroxide (H2O2)-induced House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and the cochlea of ARHL rats. Elevated apoptosis and blocked autophagic flux were uncovered in H2O2-induced HEI-OC1 cells and ARHL rats. GDF15 overexpression inhibited apoptosis and restored autophagic flux in vitro and in vivo. Meanwhile, GDF15 positively regulated SIRT1 protein expression. MSCs-GDF6 not only upregulated GDF15 and SIRT1 expression but also suppressed apoptosis and restored autophagic flux to reduce loss of HCs and hearing loss in ARHL rats. Conclusions: MSCs-GDF6 prevented loss of HCs to relieve ARHL by inhibiting apoptosis and restoring autophagic flux, likely in association with upregulation of the GDF15/SIRT1 axis.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing. How excitatory neurons (EN) acquire senescence is unclear. Here, the authors show that GDF11 in ENs slows EN senescence, brain ageing, cognitive decline and maintains lifespan, revealing a mechanism underlying EN senescence and brain ageing.