Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism ...may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases.
We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model.
FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver.
The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.
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•FGF21 and GDF15 were highly increased in MASLD following glucagon stimulation.•Plasma FGF21 and GDF15 levels correlated with insulin, but not glucagon.•FGF21 was unaffected by glucagon stimulation when insulin levels were constant.•No direct effect of glucagon on FGF21 and GDF15 secretion•The increase of FGF21 and GDF15 by glucagon in MASLD may depend on insulin.
To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four ...tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.
Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel ...anticancer agents are urgently awaited.
We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line.
We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2-M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment.
This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets.
Femoroacetabular impingement (FAI) and accompanying pathologies are associated with pain and reduced quality of life. Physical impairments can be associated with worse symptoms and may be an ...important target of rehabilitation programmes in this patient group. Knowledge regarding physical impairments in individuals with symptomatic FAI is limited.
In adults aged 18-50 years with symptomatic FAI, to: (1) identify physical impairments in range of motion (ROM), hip muscle function and functional tasks; (2) to compare physical impairments with healthy controls; and (3) to evaluate the effects of interventions targeting physical impairments.
Systematic review.
A systematic review of the literature was conducted in accordance with the PRISMA statement. The modified Downs and Black checklist was used for quality appraisal. Studies of adults aged 18-50 years with symptomatic FAI that examined ROM, hip muscle function and functional tasks were included. Standardised mean differences (SMDs) were calculated where possible or best evidence synthesis and study conclusions were presented.
22 studies fulfilled all inclusion criteria. Methodological quality was varied (47-82% using Downs and Black Appraisal Criteria). Hip joint ROM did not differ in individuals with symptomatic FAI compared with control participants. Individuals with symptomatic FAI demonstrated deficits in hip muscle strength and reduced dynamic balance on 1 leg when compared with control participants. For hip joint ROM, there were no significant within-group differences between preintervention and postintervention time points. Hip muscle strength improved significantly from prehip to posthip arthroscopy in a single case series. No randomised controlled trails evaluated the effect of different types of interventions for symptomatic patients with symptomatic FAI.
Individuals with symptomatic FAI demonstrate impairments in hip muscle strength and dynamic single leg balance. This information may assist therapists in providing targeted rehabilitation programmes for individuals with FAI and associated pathology. Further research is needed to determine whether symptomatic FAI affects other aspects of functional performance; and to evaluate whether targeted interventions are effective in symptomatic FAI.
This information may assist therapists in providing targeted rehabilitation programmes for individuals with symptomatic FAI.
Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation ...sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen
to identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of the
gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates.
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Genetic history of Native AmericansSeveral theories have been put forth as to the origin and timing of when Native American ancestors entered the Americas. To clarify this controversy, Raghavan et ...al. examined the genomic variation among ancient and modern individuals from Asia and the Americas. There is no evidence for multiple waves of entry or recurrent gene flow with Asians in northern populations. The earliest migrations occurred no earlier than 23,000 years ago from Siberian ancestors. Amerindians and Athabascans originated from a single population, splitting approximately 13,000 years ago.Science, this issue 10.1126/science.aab3884 How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 ...s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying ...genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at ∼550 000 markers across the autosomal genome. ...We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of risk-conferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.
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