A5025554378- Diabetes Treatment and Management
- Diet and metabolism studies
- Neuropeptides and Animal Physiology
- Adipose Tissue and Metabolism
- Receptor Mechanisms and Signaling
- Regulation of Appetite and Obesity
- Bat Biology and Ecology Studies
- Liver Disease Diagnosis and Treatment
- Sirtuins and Resveratrol in Medicine
- Diet, Metabolism, and Disease
- Metabolism, Diabetes, and Cancer
- PARP inhibition in cancer therapy
- Physiological and biochemical adaptations
- CRISPR and Genetic Engineering
- Biochemical and Molecular Research
- Gene Regulatory Network Analysis
- Thermoregulation and physiological responses
- Advanced Glycation End Products research
- Neurobiology and Insect Physiology Research
- Chronic Kidney Disease and Diabetes
- Circadian rhythm and melatonin
- Biochemical effects in animals
- Effects of Environmental Stressors on Livestock
- RNA modifications and cancer
- Pain Mechanisms and Treatments
Philipps University of Marburg
1999-2022
Sanofi (Germany)
2010-2022
Sanofi (France)
2020
Sanofi (United States)
2020
Helmholtz Zentrum München
2010-2016
Technical University of Munich
2012
Weihenstephan-Triesdorf University of Applied Sciences
2012
Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight improved glucose control rodent models. We developed SAR441255, a synthetic peptide agonist GLP-1, GCG, GIP receptors, structurally based on exendin-4 sequence. SAR441255 displays high potency with balanced activation all three target receptors. In animal models, metabolic outcomes were...
Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has potential to lead a novel therapy principle for treatment diabesity. Here, we report series peptides with dual activity on these receptors that were discovered by rational design. On basis sequence analysis structure-based design, structural elements engineered into selective GLP-1 agonist exendin-4, resulting in hybrid potent GLP-1/glucagon activity. Detailed structure-activity relationship data are shown....
The CB1 receptor antagonist, rimonabant, affects the endocannabinoid system and causes a sustained reduction in body weight (BW) despite transient nature of food intake. Therefore, multiple-dose study, female candy-fed Wistar rats were treated with rimonabant (10 mg/kg) matched pair-fed to distinguish between hypophagic action hypothesized effects on energy expenditure. Within first week treatment, reduced BW nearly levels standard rat chow-fed rats. Evaluation balance (energy expenditure...
Abstract Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of methyl group from co-factor S-adenosyl-L-methionine (SAM) onto substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity type-2 diabetes. Here we report small molecule analog NA, JBSNF-000088, inhibits activity, reduces levels drives insulin sensitization, glucose modulation body weight reduction in...
Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide N-methyltransferase (NNMT) in high-fat diet (HFD)–fed mice has been reported to reduce weight gain and plasma insulin levels improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout (NNMT−/−), we tested the hypothesis that Nnmt deletion protects against diet-induced obesity its metabolic consequences males females on obesity-inducing diets. We also examined samples from a human reduction (WR) study for adipose (aNNMT)...
Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 with regard treatment obesity diabetes. We describe novel exendin-4 based designed an activity ratio favoring versus receptor. As result iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), design synthesis, experimental activity, solubility profiling, a candidate molecule was identified. SAR...
Aim We performed acute and chronic studies in healthy diet‐induced obese animals using mouse‐specific or monkey‐specific dual GLP‐1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control insulin secretion. The selective GLP‐1R agonist liraglutide was used as comparator. Methods were tested lean wild type, knockout mice at different doses. A study DIO the effect consumption total energy expenditure (TEE) diabetic monkeys with a focus weight intake....
To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon (GCGR) and glucose-dependent insulinotropic peptide (GIPR), individually in combination, a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) fibrosis order decipher contribution their activities potential additive effects improving systemic hepatic metabolism.We induced NASH by pre-feeding C57BL/6J mice diet rich fat, fructose cholesterol for 36 weeks. This was followed 8 weeks treatment...
Background In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence chronic-degenerative diseases, ultimately leading to increased lifespan. Methodology/Principal Findings Here we show that knockout mice for Eps8, regulator actin dynamics, display reduced body weight, partial resistance age- or diet-induced obesity, overall improved status. Alteration in liver gene expression profile, behavior metabolism point calorie...
Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development functioning of central neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient have higher body weight due to increased adipose tissue mass. several feeding paradigms, consumed more food than wild-type (WT) controls, this consumption was primarily driven by calories rather palatability....
SUMMARY Dormice voluntarily enter torpor at ambient temperatures ranging between 0–28°C. This study describes heart rate, ventilation frequency,O2-consumption (defined as metabolic rate),CO2-production and body temperature during entrance into torpor. Their temporal relationship was analysed the time course of depression different temperatures. Body rate were measured in unrestrained dormice with implanted transmitter. Ventilation frequency monitored by total plethysmography or infrared...
Male obese Zucker Diabetic Fatty (ZDF) rats develop type 2 diabetes around eight weeks of age, and are widely used as a model for human its complications. The objective the study was to test whether complications manifested in kidney nerves ZDF really correspond diabetic their being related hyperglycaemic state. Four groups were used. One lean (Fa/?) one (fa/fa) untreated group served non-diabetic controls. In two further rats, prevented by pioglitazone or delayed food restriction. All...
Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator that catalyzes the methylation of nicotinamide (Nam) using co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (MNA). Overexpression NNMT and presence active metabolite MNA associated with number diseases including disorders. We conducted high-throughput screening campaign led identification tricyclic core as potential small molecule inhibitor series. Elaborate medicinal chemistry efforts were undertaken hundreds...
Obese Zucker diabetic fatty (ZDF) rats are used as a type-2 diabetes model for microvascular complications. In order to study retinopathy in this model, changes retinal vasculature were analyzed by quantitative morphometry and related expression of 46 selected genes that microfluidic card PCR technology. At 3 months age, obese animals had developed stable hyperglycemia (20.7 ± 1.3 mmol/L plasma glucose vs. 6.5 0.1 lean). Hyperinsulinemia initially presented at 2 (10.5 0.7 μg/L insulin 0.2...
G protein-coupled receptor 17 (GPR17) was recently reported to be a Foxo1 target in agouti-related peptide (AGRP) neurons. Intracerebroventricular injection of GPR17 agonists induced food intake, whereas administration an antagonist the reduced feeding. These data lead conclusion that pharmacological modulation has therapeutic potential treat obesity. Here we report mice deficient Gpr17 (Gpr17(-/-)) have similar intake and body weight compared with their wild-type littermates. Gpr17(-/-)...
We assessed the therapeutic contribution of individual components glucagon-like peptide-1 receptor (GLP-1R) and glucagon (GCGR) agonists alone in combination upon energy homeostasis glycemic control diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges selective were established through a dose-finding study, followed by 6-week chronic study. Repeated subcutaneous administration GCGR agonist (30 µg/kg once daily) did not affect food intake or body weight,...
Aims Intensive glycaemic control in type 2 diabetes achieved by insulin is generally accompanied body weight gain. This study was performed to emphasize the meaning of caloric analysis urine and faeces for energy balance. Methods We measured energetic loss via during antihyperglycaemic treatment male obese Zucker diabetic fatty ( ZDF ) rats. Rats were treated 10 days with sodium–glucose‐linked transporter‐2 SGLT2 inhibitor AVE2268 , glargine, GLP ‐1 receptor agonist lixisenatide combination...
The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function this gene is available, their roles during adulthood. Here, we present first Scube3 mutant mouse line (Scube3N294K/N294K), clearly shows phenotypic alterations by carrying a missense mutation in exon 8, thus contributes to our understanding...