Search

Obesity represents a worldwide health challenge, and the condition is accompanied by elevated risk of cardiovascular diseases caused by metabolic dysfunction and proinflammatory adipokines. Among those, the immune-modulatory cathelicidin antimicrobial peptide (human: CAMP; murine: CRAMP) might contribute to the interaction of the innate immune system and metabolism in these settings. We investigated systemic CAMP/CRAMP levels in experimental murine models of atherosclerosis, myocardial infarction and cardiovascular patients. Atherosclerosis was induced in low-density lipoprotein receptor-deficient (Ldlr−/−) mice by high-fat diet (HFD). C57BL/6J wild-type mice were subjected to myocardial infarction by permanent or transient left anterior descending (LAD)-ligation. Cramp gene expression in murine organs and tissues was investigated via real-time PCR. Blood samples of 234 adult individuals with or without coronary artery disease (CAD) were collected. Human and murine CAMP/CRAMP serum levels were quantified by ELISA. Atherosclerotic mice exhibited significantly increased CRAMP serum levels and induced Cramp gene expression in the spleen and liver, whereas experimental myocardial infarction substantially decreased CRAMP serum levels. Human CAMP serum quantities were not significantly affected by CAD while being correlated with leukocytes and pro-inflammatory cytokines. Our data show an influence of cathelicidin in experimental atherosclerosis, myocardial infarction, as well as in patients with CAD. Further studies are needed to elucidate the pathophysiological mechanism. [ABSTRACT FROM AUTHOR]

The pleiotropic chemokine chemerin is involved in multiple processes in metabolism and inflammation. The present study aimed to elucidate its regulation in morbid obesity and during therapy-induced rapid weight loss. A total of 128 severely obese patients were enrolled, and their basal anthropometric and clinical parameters were assessed. In total, 64 individuals attended a conservative 12-month weight loss program that included a low calorie-formula diet (LCD), and 64 patients underwent bariatric surgery (Roux-en-Y gastric bypass, RYGB). Blood serum was obtained at study baseline and at follow-up visits after 3, 6, and 12 months. Systemic chemerin concentrations, as well as metabolic and immunological parameters, were quantified. During the 12-month period studied, serum chemerin levels decreased significantly with weight loss after bariatric surgery, as well as with conservative low calorie therapy; however, the effects of RYGB were generally stronger. No substantial associations of systemic chemerin concentrations with therapy-induced improvement of type 2 diabetes and with indicators of liver function and fibrosis were observed. We conclude that systemic chemerin levels decrease in obese individuals during weight loss, regardless of the therapeutic strategy. A potential involvement in weight loss-associated improvement of metabolic disorders and liver fibrosis remains to be further investigated. [ABSTRACT FROM AUTHOR]

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2− breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study's inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2− eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2− breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2− eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Understanding the complex interactions between metabolism and the immune system ("metaflammation") is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP, therefore, might play a role as an adipokine in metaflammation and adipose inflammation. TNFα, cell-free nucleic acids (cfDNA), and toll-like receptor (TLR) 9 are components of the innate immune system and are functionally active in adipose tissue. The aim of the present study was to investigate the impact of TNFα and cfDNA on CAMP expression in adipocytes. Since cfDNA acts as a physiological TLR9 agonist, we additionally investigated TLR9-mediated CAMP regulation in adipocytes and adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. Adipocyte inflammation was induced in vitro by TNFα and cfDNA stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. In primary adipocytes of wildtype and TLR9 KO mice, CAMP gene expression was quantified by real-time PCR. CAMP gene expression was considerably increased in 3T3-L1 and SGBS adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was effectively antagonized by inhibition of PI3K signaling. Cell-free nucleic acids (cfDNA) significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intra-abdominal/visceral adipose tissues. Male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP gene expression levels in primary adipocytes did not significantly differ between wildtype and TLR9 KO mice. These findings suggest a regulatory role of inflammatory mediators, such as TNFα and cfDNA, in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity. [ABSTRACT FROM AUTHOR]

Recent investigation has revealed the significant role of Cathelicidin antimicrobial peptide (CAMP) in infection defense and innate immunity processes in adipose tissue. Meanwhile, knowledge of its regulation and functions in metabolic contexts as an adipokine remains sparce. The present study investigated the postprandial regulation of circulating CAMP levels during oral glucose tolerance tests (OGTTs). Eighty-six metabolically healthy volunteers participated in a standardized 75 g-2 h-OGTT setting. The effects of exogenous glucose, insulin, and incretins on CAMP expression in human adipocyte culture (cell-line SGBS) were studied in vitro. CAMP concentrations in blood serum samples were measured by ELISA techniques and adipocyte gene expression levels were quantified by real-time PCR. Of note, base-line CAMP serum quantities were negatively correlated with HDL cholesterol levels as well as with the anti-inflammatory adipokine adiponectin. During the 2 h following glucose ingestion, a significant rise in circulating CAMP concentrations was observed in considerable contrast to reduced quantities of fatty acid binding proteins (FABP) 2 and 4 and dipeptidyl peptidase 4 (DPP4). In SGBS adipocytes, neither differing glucose levels nor insulin or incretin treatment significantly induced CAMP mRNA levels. According to our data, glucose represents a positive postprandial regulator of systemic CAMP. This effect apparently is not mediated by the regulatory impact of glucose metabolism on adipocyte CAMP expression. [ABSTRACT FROM AUTHOR]

The aggregation of amyloid- β (A β) peptides, particularly of A β 1 − 42 , has been linked to the pathogenesis of Alzheimer's disease. In this study, we focus on the conformational change of A β 1 − 42 in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in A β by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in A β 1 − 42 in solution to more compact states arising from stable β -hairpin formation when A β 1 − 42 is in the vicinity of a GAG molecule, and even more compact states characterized by a α -helix or β -sheet structures when A β 1 − 42 interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the A β 1 − 42 /GAG and A β 1 − 42 /POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of A β 1 − 42 , in the case of GAG there are hardly any intermolecular A β 1 − 42 –GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a β -hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the A β peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils. [ABSTRACT FROM AUTHOR]

Introduction: Obesity and related diseases are among the main public health issues in the western world. They are thought to be caused by a state of chronic, low-grade inflammation. Cathelicidin antimicrobial peptide (CAMP) was recently discovered to be expressed and secreted by adipocytes. Representing a novel immunomodulatory adipokine, CAMP might play an important role in the complex interaction between metabolism and inflammation. Methods: In a cohort of 80 volunteers, serum samples were collected prior to, and 2 h, 4 h, and 6 h after, oral lipid ingestion. CAMP, fatty acid binding proteins 2 and 4 (FABP-2/-4), and dipeptidylpeptidase-4 (DPP-4) serum concentrations were measured via ELISA. Human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes were treated with free fatty acids, and gene expression levels of CAMP, FABP-4, and DPP-4 were quantified by RT-PCR. Results: The mean base-line CAMP serum concentration was 55.78 ± 29.26 ng/mL, with a range of 10.77–146.24 ng/mL. Interestingly, CAMP serum levels were positively correlated with LDL cholesterol, but negatively correlated with HDL cholesterol and adiponectin. Men exhibited higher CAMP serum concentrations than women, an effect apparently linked to oral contraception in the majority of female participants. In both genders, CAMP serum concentrations significantly decreased in a stepwise manner 4 h and 6 h after oral lipid ingestion. This decline was paralleled by a rise of serum bile acid and triglyceride levels upon lipid ingestion. In human SGBS adipocytes, treatment with free fatty acids did not affect CAMP gene expression, but increased FABP-4 gene expression. Conclusions: In conclusion, systemic levels of the antimicrobial peptide and novel adipokine CAMP are significantly decreased upon oral lipid ingestion. While this decline might be linked to the simultaneous increase in bile acids, the underlying mechanisms remain to be elucidated. Furthermore, CAMP might indicate a putative novel cardiovascular biomarker of both inflammatory and metabolic relevance in metaflammation and adipose inflammation. [ABSTRACT FROM AUTHOR]

Allocation of morbidly obese patients to either conservative therapy options—such as lifestyle intervention and/or low-calorie diet (LCD)—or to bariatric surgery—preferably sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB)—represents a crucial decision in order to obtain sustainable metabolic improvement and weight loss. The present study encompasses 160 severely obese patients, 81 of whom participated in an LCD program, whereas 79 underwent RYGB surgery. The post-interventional dynamics of physiologically relevant adipokines and hepatokines (ANGPTL4, CCL5, GDF15, GPNMB, IGFBP6), as well as their correlation with fat mass reduction and improvement of liver fibrosis, were analyzed. Systemic GDF15 was characterized as an excellent predictive marker for hepatic fibrosis as well as type 2 diabetes mellitus. Of note, baseline GDF15 serum concentrations were positively correlated with NFS and HbA1c levels after correction for BMI, suggesting GDF15 as a BMI-independent marker of hepatic fibrosis and T2D in obese individuals. Specific GDF15 cut-off values for both diseases were calculated. Overall, the present data demonstrate that circulating levels of specific adipokines and hepatokines are regulated with therapy-induced fat loss and metabolic improvement and might, therefore, serve as biomarkers for the success of obesity therapy strategies. [ABSTRACT FROM AUTHOR]

Endosome-localized Toll-like receptors (TLRs) 3 and 9 are expressed and functionally active in adipocytes. The functionality and role of TLR7 in adipocyte biology and innate immunity of adipose tissue (AT) is poorly characterized. We analyzed TLR7 mRNA and protein expression in murine 3T3-L1 and primary adipocytes, in co-cultures of 3T3-L1 adipocytes with murine J774A.1 monocytes and in human AT. The effects of TLR7 agonists imiquimod (IMQ) and cell-free nucleic acids (cfDNA) on adipokine concentration in cell-culture supernatants and gene expression profile were investigated. We found that TLR7 expression is strongly induced during adipocyte differentiation. TLR7 gene expression in adipocytes and AT stroma-vascular cells (SVC) seems to be independent of TLR9. IMQ downregulates resistin concentration in adipocyte cell-culture supernatants and modulates gene expression of glucose transporter Glut4. Adipocyte-derived cfDNA reduces adiponectin and resistin in cell-culture supernatants and potentially inhibits Glut4 gene expression. The responsiveness of 3T3-L1 adipocytes to imiquimod is preserved in co-culture with J774A.1 monocytes. Obesity-related, adipocyte-derived cfDNA engages adipocytic pattern recognition receptors (PRRs), modulating AT immune and metabolic homeostasis during adipose inflammation. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes mellitus (T2D) represent important comorbidities of the metabolic syndrome, which are associated with non-alcoholic fatty liver disease (NAFLD)-related hepatic fibrosis. In total, 160 morbidly obese patients—81 following a low-calorie formula diet (LCD) program and 79 undergoing bariatric surgery (Roux-en-Y gastric bypass, RYGB)—were examined for anthropometric and metabolic parameters at base-line and during 12 months of weight loss, focusing on a putative co-regulation of T2D parameters and liver fibrosis risk. High NAFLD fibrosis scores (NFS) before intervention were associated with elevated HbA1c levels and T2D. Loss of weight and body fat percentage (BFL) were associated with improved glucose and lipid metabolism and reduced risk of NAFLD-related fibrosis, with particularly beneficial effects by RYGB. Both T2D improvement and NFS decrease were positively associated with high BFL. A highly significant correlation of NFS reduction with BFL was restricted to male patients while being absent in females, accompanied by generally higher BFL in men. Overall, the data display the relation of BFL, T2D improvement, and reduced NAFLD-related fibrosis risk during weight loss in morbidly obese individuals induced by diet or RYGB. Furthermore, our data suggest a considerable sexual dimorphism concerning the correlation of fat loss and improved risk of liver fibrosis. [ABSTRACT FROM AUTHOR]

The C1q/TNF-related protein 3 (CTRP3) represents a pleiotropic adipokine reciprocally associated with obesity and type 2 diabetes mellitus and exhibits anti-inflammatory properties in relation to lipopolysaccharides (LPS)-mediated effects in adipocytes, as well as monocytes/macrophages. Here, we focused on the influence of CTRP3 on LPS-mediated effects in endothelial cells in order to expand the understanding of a possible anti-inflammatory function of CTRP3 in a setting of endotoxemia. An organ- and tissue-specific expression analysis by real-time PCR revealed a considerable Ctrp3 expression in various adipose tissue compartments; however, higher levels were detected in the aorta and in abundantly perfused tissues (bone marrow and the thyroid gland). We observed a robust Ctrp3 expression in primary endothelial cells and a transient upregulation in murine endothelial (MyEND) cells by LPS (50 ng/mL). In MyEND cells, CTRP3 inhibited the LPS-induced expression of interleukin (Il)-6 and the tumor necrosis factor (Tnf)-α, and suppressed the LPS-dependent expression of the major endothelial adhesion molecules Vcam-1 and Icam-1. The LPS-induced adhesion of monocytic cells to an endothelial monolayer was antagonized by CTRP3. In C57BL/6J mice with an LPS-induced systemic inflammation, exogenous CTRP3 did not affect circulating levels of TNF-α, ICAM-1, and VCAM-1. In conclusion, we characterized CTRP3 beyond its function as an adipokine in a setting of vascular inflammation. CTRP3 inhibited LPS-induced endothelial expression of adhesion molecules and monocyte cell adhesion, indicating an important vascular anti-inflammatory role for CTRP3 in endotoxemia. [ABSTRACT FROM AUTHOR]

Bariatric surgery has emerged as an effective treatment option in morbidly obese patients with non-alcoholic fatty liver disease (NAFLD). However, worsening or new onset of non-alcoholic steatohepatitis (NASH) and fibrosis have been observed. Caspase-cleaved keratin 18 (ccK18) has been established as a marker of hepatocyte apoptosis, a key event in NASH development. Thus, ccK18 measurements might be feasible to monitor bariatric surgery patients. Clinical data and laboratory parameters were collected from 39 patients undergoing laparoscopic Roux-en-Y gastric bypass at six timepoints, prior to surgery until one year after the procedure. ccK18 levels were measured and a high-throughput analysis of serum adipokines and cytokines was carried out. Half of the cohort's patients (20/39) presented with ccK18 levels indicative of progressed liver disease. 21% had a NAFLD-fibrosis score greater than 0.676, suggesting significant fibrosis. One year after surgery, a mean weight loss of 36.87% was achieved. Six and twelve months after surgery, ccK18 fragments were significantly reduced compared to preoperative levels (p < 0.001). Yet nine patients did not show a decline in ccK18 levels ≥ 10% within one year postoperatively, which was considered a response to treatment. While no significant differences in laboratory parameters or ccK18 could be observed, they presented with a greater expression of leptin and fibrinogen before surgery. Consecutive ccK18 measurements monitored the resolution of NAFLD and identified non-responders to bariatric surgery with ongoing liver injury. Further studies are needed to elicit the pathological mechanisms in non-responders and study the potential of adipokines as prognostic markers. [ABSTRACT FROM AUTHOR]

CTRP-3 (C1q/TNF-related protein-3) is an adipokine with endocrine and immunological function. The impact of adipocyte CTRP-3 production on systemic CTRP-3 concentrations and on adipocyte biology is unknown. A murine model of adipocyte CTRP-3 knockout (KO) was established (via the Cre/loxP system). Serum adipokine levels were quantified by ELISA and adipose tissue (AT) gene expression by real-time PCR. Preadipocytes were isolated from AT and differentiated into adipocytes. Comparative transcriptome analysis was applied in adipocytes and liver tissue. Body weight and AT mass were reduced in CTRP-3 KO mice together with decreased serum leptin. In primary cells from visceral AT of KO mice, expression of adiponectin, progranulin, and resistin was induced, while peroxisome proliferator activated receptor γ (PPARγ) was decreased. M1/M2 macrophage polarization markers were shifted to a more anti-inflammatory phenotype. CTRP-3 expression in AT did not contribute to serum concentrations. AT and liver morphology remained unaffected by CTRP-3 KO. Myelin transcription factor 1-like (Myt1l) was identified as a highly upregulated gene. In conclusion, adipocyte CTRP-3 has a role in adipogenesis and AT weight gain whereas adipocyte differentiation is not impaired by CTRP-3 deficiency. Since no effects on circulating CTRP-3 levels were observed, the impact of adipocyte CTRP-3 KO is limited to adipose tissue. Modified AT gene expression indicates a rather anti-inflammatory phenotype. [ABSTRACT FROM AUTHOR]

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system. [ABSTRACT FROM AUTHOR]

Eukaryotic cells determine the protein output of their genetic program by regulating mRNA transcription, localization, translation and turnover rates. This regulation is accomplished by an ensemble of RNA-binding proteins (RBPs) that bind to any given mRNA, thus forming mRNPs. Poly(A) binding proteins (PABPs) are prominent members of virtually all mRNPs that possess poly(A) tails. They serve as multifunctional scaffolds, allowing the recruitment of diverse factors containing a poly(A)-interacting motif (PAM) into mRNPs. We present the crystal structure of the variant PAM motif (termed PAM2w) in the N-terminal part of the positive translation factor LARP4B, which binds to the MLLE domain of the poly(A) binding protein C1 cytoplasmic 1 (PABPC1). The structural analysis, along with mutational studies in vitro and in vivo, uncovered a new mode of interaction between PAM2 motifs and MLLE domains. [ABSTRACT FROM AUTHOR]

While light-emitting nanostructures composed of group-IV materials fulfil the mandatory compatibility with CMOS-fabrication methods, factors such as the structural stability of the nanostructures upon thermal annealing, and the ensuing photoluminescence (PL) emission properties, are of key relevance. In addition, the possibility of improving the PL efficiency by suitable post-growth treatments, such as hydrogen irradiation, is important too. We address these issues for self-assembled Ge quantum dots (QDs) that are co-implanted with Ge ions during their epitaxial growth. The presence of defects introduced by the impinging Ge ions results in pronounced PL-emission at telecom wavelengths up to room temperature (RT) and above. This approach allows us to overcome the severe limitations of light generation in the indirect-band-gap group-IV materials. By performing in-situ annealing, we demonstrate a high PL-stability of the defect-enhanced QD (DEQD) system against thermal treatment up to 600 °C for at least 2 h, even though the Ge QDs are structurally affected by Si/Ge intermixing via bulk diffusion. The latter, in turn, allows for emission tuning of the DEQDs over the entire telecom wavelength range from 1.3 µm to 1.55 µm. Two quenching mechanisms for light-emission are discussed; first, luminescence quenching at high PL recording temperatures, associated with the thermal escape of holes to the surrounding wetting layer; and second, annealing-induced PL-quenching at annealing temperatures >650 °C, which is associated with a migration of the defect complex out of the QD. We show that low-energy ex-situ proton irradiation into the Si matrix further improves the light emission properties of the DEQDs, whereas proton irradiation-related optically active G-centers do not affect the room temperature luminescence properties of DEQDs. [ABSTRACT FROM AUTHOR]

The authors investigated the effect of an applied high voltage (1 kV) across the thickness of a soda-lime glass substrate of Cu(In,Ga)Se2 (CIGS) thin-film solar cells. Two types of CIGS cells were tested, differing only in the deposition process of the molybdenum (Mo) back contact. Whilst one cell type was susceptible to potential induced degradation (PID), the other exhibited highly increased stability against PID. PID occurs for PID-susceptible cells after the transfer of a certain amount of charge through the soda-lime glass substrate when the Mo back contact of the cell operates as a cathode (negatively biased versus backside of the substrate). Capacitance–voltage and electron-beam-induced current measurements showed an enlarged space charge region expanding to the Mo back contact and a lowered doping density by a negative potential for PID-susceptible cells. Glow discharge optical emission spectroscopy (GDOES) revealed an accumulation of sodium (Na) in the solution-grown CdS buffer layer and a segregation on the surface of the ZnO:Al window layer for higher charges for PID-susceptible cells. Cells with increased PID immunity did not show an increase of Na for charges up to around 9 mC/cm². We demonstrate that it is possible to improve the PID stability of CIGS solar cells by modification of the molybdenum back contact. [ABSTRACT FROM AUTHOR]

Global agreements like the Sustainable Development Goals (SDGs) and Achi Biodiversity Targets (ABTs) aim to secure human well-being and to protect biodiversity, but little progress has been made in reaching these aims. The key role of biodiversity in securing human well-being is rarely considered a priority – instead short-term economic profits benefiting a few are prioritized. Particularly where local livelihoods rely on resources of protected areas for immediate survival, top-down enforced biodiversity conservation often increases social inequality, hunger and poverty and thus regularly fails. Identifying key knowledge gaps helps to adjust political priority setting and investment strategies to assess conservation threats and improve natural resource management. Since acting usually occurs at a local or regional scale, we focused on a priority conservation area in one of the world's poorest countries — the dry deciduous forests of western Madagascar. We aimed to identify key knowledge gaps in this area which need to be filled to better protect biodiversity and simultaneously ensure well-being of the local poor. We consulted 51 predominantly Malagasy experts using questionnaires. These questionnaires listed 71 knowledge gaps we collated from the literature which the experts were asked to rank by importance. Experts were encouraged to list additional knowledge gaps. Averaging the scores of all experts, we identified the top 10 knowledge gaps. Two political knowledge gaps addressing the need to determine strategies which improve law enforcement and reduce corruption ranked highest, followed by an ecological one concerning appropriate restoration and a socio–economic one regarding economic benefits locals gain from biodiversity. The general knowledge gap perceived as most important addressed strategies for long-term funding. Only one additional knowledge gap was identified: the impact of climate change-driven human migration from southwestern to central western Madagascar on socio–economic problems and its impacts on natural resources We linked the identified top 10 knowledge gaps as well as the additional knowledge gap suggested by experts to the SDGs, ABTs and 2 °C target of the Paris Climate Agreement, and discussed why these gaps were considered a priority. This research highlights important ecological, socio–economic and political research priorities and provides guidelines for policy makers and funding organizations. [ABSTRACT FROM AUTHOR]