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Aims Multiple sclerosis (MS) still maintains increasing prevalence and poor prognosis, while glucagon‐like peptide‐1 receptor (GLP‐1R) agonists show excellent neuroprotective capacities recently. Thus, we aim to evaluate whether the GLP‐1R agonist liraglutide (Lira) could ameliorate central nervous system demyelination and inflammation. Methods The therapeutic effect of Lira was tested on experimental autoimmune encephalitis (EAE) in vivo and a microglia cell line BV2 in vitro. Results Lira administration could ameliorate the disease score of EAE mice, delay the disease onset, ameliorate pathological demyelination and inflammation score in lumbar spinal cord, reduce pathogenic T helper cell transcription in spleen, restore phosphorylated adenosine monophosphate‐activated protein kinase (pAMPK) level, autophagy level, and inhibit pyroptosis‐related NLR family, pyrin domain‐containing protein 3 (NLRP3) pathway in lumbar spinal cord. Additionally, cell viability test, lactate dehydrogenase release test, and dead/live cell staining test for BV2 cells showed Lira could not salvage BV2 from nigericin‐induced pyroptosis significantly. Conclusion Lira has anti‐inflammation and anti‐demyelination effect on EAE mice, and the protective effect of Lira in the EAE model may be related to regulation of pAMPK pathway, autophagy, and NLRP3 pathway. However, Lira treatment cannot significantly inhibit pyroptosis of BV2 cells in vitro. Our study provides Lira as a potential candidate for Multiple Sclerosis treatment. Liraglutide (Lira) has neuroprotective effect on experimental autoimmune encephalitis (EAE) mice, and the protective effect of Lira in the EAE model may be related to regulation of pAMPK level, autophagy, and NLRP3 pathway. However, Lira treatment cannot significantly inhibit pyroptosis of BV2 cells in vitro.

Background As glucocorticoids induce muscle atrophy during the treatment course of polymyositis (PM), novel therapeutic strategy is awaited that suppresses muscle inflammation but retains muscle strength. We recently found that injured muscle fibres in PM undergo FASLG‐mediated necroptosis, a form of regulated cell death accompanied by release of pro‐inflammatory mediators, contributes to accelerate muscle inflammation and muscle weakness. Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have pleiotropic actions including anti‐inflammatory effects, prevention of muscle atrophy, and inhibition of cell death, in addition to anti‐diabetic effect. We aimed in this study to examine the role of GLP‐1R in PM and the effect of a GLP‐1R agonist on in vivo and in vitro models of PM. Methods Muscle specimens of PM patients and a murine model of PM, C protein‐induced myositis (CIM), were examined for the expression of GLP‐1R. The effect of PF1801, a GLP‐1R agonist, on CIM was evaluated in monotherapy or in combination with prednisolone (PSL). As an in vitro model of PM, C2C12‐derived myotubes were treated with FASLG to induce necroptosis. The effect of PF1801 on this model was analysed. Results GLP‐1R was expressed on the inflamed muscle fibres of PM and CIM. The treatment of CIM with PF1801 in monotherapy (PF) or in combination with PSL (PF + PSL) suppressed CIM‐induced muscle weakness (grip strength, mean ± SD (g); PF 227 ± 6.0 (P < 0.01), PF + PSL 224 ± 8.5 (P < 0.01), Vehicle 162 ± 6.0) and decrease in cross‐sectional area of muscle fibres (mean ± SD (μm2); PF 1896 ± 144 (P < 0.05), PF + PSL 2018 ± 445 (P < 0.01), Vehicle 1349 ± 199) as well as the severity of histological inflammation scores (median, interquartile range; PF 0.0, 0.0–0.5 (P < 0.05), PF + PSL 0.0, 0.0–0.0 (P < 0.01), Vehicle 1.9, 1.3–3.3). PF1801 decreased the levels of inflammatory mediators such as TNFα, IL‐6, and HMGB1 in the serum of CIM. PF1801 inhibited necroptosis of the myotubes in an AMP‐activated protein kinase (AMPK)‐dependent manner. PF1801 activated AMPK and decreased the expression of PGAM5, a mitochondrial protein, which was crucial for necroptosis of the myotubes. PF1801 promoted the degradation of PGAM5 through ubiquitin‐proteasome activity. Furthermore, PF1801 suppressed FASLG‐induced reactive oxygen species (ROS) accumulation in myotubes, also crucial for the execution of necroptosis, thorough up‐regulating the antioxidant molecules including Nfe2l2, Hmox1, Gclm, and Nqo1. Conclusions GLP‐1R agonist could be a novel therapy for PM that recovers muscle weakness and suppresses muscle inflammation through inhi biting muscle fibre necroptosis.

Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

ABSTRACT For the treatment of Type 2 Diabetes, high efficacy approaches such as Glucagon‐like peptide 1 (GLP‐1)‐based therapies are recommended for glucose control. Prediction of the clinical outcome of these therapies on glucose and hemoglobin A1c (HbA1c), using early available pharmacokinetic and in vitro efficacy information, can be a valuable tool for compound selection and supporting drug development. Our previously developed glucose homeostasis model (the 4GI model) is a systems model that is able to quantify drug effects on glucose based on in vitro potency and PK information. In this research, the model was coupled to an existing integrated glucose‐red blood cell‐HbA1c (IGRH) model for predicting the effects of GLP‐1 and GLP‐1/glucagon (dual) receptor agonists, liraglutide and cotadutide, on glucose and HbA1c. The 4GI model was validated for predicting 24‐h glucose (Cglc,av) with minimal model calibration using short‐term Ph2a continuous glucose monitoring (CGM) data. Subsequently, the predicted Cglc,av served as input for the HbA1c model to assess the predictiveness of the combined 4GI‐HbA1c model on HbA1c. The resulting combined model was used in cotadutide's clinical development by providing predictive insights into the 26 weeks glucose and HbA1c dynamics of the Ph2b study prior to its initiation. Retrospective analysis showed that the model adequately predicted the effect of cotadutide and liraglutide on fasting plasma glucose and HbA1c (Root Means Square Percent Error (RMSPE) 5.9% and 13%, respectively). This demonstrates the potential of the 4GI‐HbA1c systems model as a valuable tool in supporting the clinical development of novel GLP‐1 and/or glucagon agonists. A combined systems model (4GI‐HbA1c) was developed to predict glucose and HbA1c responses to GLP‐1 and GLP‐1/glucagon receptor agonists using early pharmacokinetic and in vitro efficacy data. Validated with short‐term CGM data, the model accurately predicted 26‐week clinical outcomes for liraglutide and cotadutide, demonstrating its value in supporting drug development and compound selection.

ABSTRACT Background and Aim Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists are well‐established therapies for obesity and type 2 diabetes mellitus (T2DM). Emerging evidence also suggests their potential role in managing obstructive sleep apnea (OSA). This study aimed to investigate the association between GLP‐1R agonists and OSA using genetic evidence. Methods Cis‐expression quantitative trait loci (cis‐eQTLs) associated with the GLP1R gene were identified and used as genetic proxies for GLP‐1R agonist exposure. To validate the selected genetic instruments, positive control analyses were conducted for T2DM and body mass index (BMI). Mendelian randomization was employed to evaluate the effect of genetically proxied GLP‐1R agonists on OSA. OSA data were obtained from FinnGen Release 11 (R11), comprising 50,200 cases and 401,484 controls of European ancestry. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by heterogeneity tests and sensitivity analyses. Results IVW analysis showed that genetically predicted GLP‐1R agonist exposure was associated with a reduction in BMI (β = −0.063, 95% confidence interval [CI]: −0.10 to −0.03, p = 8.43 × 10−4) and a decreased risk of T2DM (odds ratio [OR] = 0.80, 95% CI: 0.65 to 0.98, p = 0.032), supporting the validity of the genetic instruments. Notably, GLP‐1R agonists were also associated with a significantly lower risk of OSA (OR = 0.83, 95% CI: 0.76 to 0.91, p = 6.15 × 10−5). No evidence of heterogeneity or horizontal pleiotropy was detected, and leave‐one‐out analysis confirmed the robustness of the findings. Conclusion This study provides genetic evidence supporting the protective role of GLP‐1R agonists against OSA, highlighting their potential as a therapeutic strategy for OSA management.

In diabetes mellitus (DM), the kidneys are exposed to increased levels of hyperglycemia‐induced oxidative stress. Elevated amounts of reactive oxygen species (ROS) are believed to provoke ultrastructural changes in kidney tissue and can eventually result in DM late complications such as diabetic nephropathy. While it is reported that glucagon‐like peptide 1 receptors (GLP‐1R) are present in the kidney vasculature, the effects of GLP‐1 on the kidney proteome in DM is not well described. Thus, we set out to investigate potential effects on the proteomic level. Here the effects of GLP‐1R agonism using the GLP‐1 analogue liraglutide are studied in the kidneys of streptozotocin (STZ)‐treated mice (n = 6/group) by label‐free shotgun mass spectrometry (MS) and targeted MS. Unsupervised and supervised multivariate analyses are followed by one‐way ANOVA. Shotgun MS data of vehicle and liraglutide‐treated mouse groups are separated in the supervised multivariate analysis and separation is also achieved in the subsequent unsupervised multivariate analysis using targeted MS data. The mouse group receiving the GLP‐1R agonist liraglutide has increased protein abundances of glutathione peroxidase‐3 (GPX3) and catalase (CATA) while the abundances of neuroplastin (NPTN) and bifunctional glutamate/proline–tRNA ligase (SYEP) are decreased compared to the STZ vehicle mice. The data suggest that GLP‐1R agonism mainly influences abundances of structurally involved proteins and proteins involved in oxidative stress responses in the STZ mouse kidney. The changes could be direct effects of GLP‐1R agonism in the kidneys or indirectly caused by a systemic response to GLP‐1R activation. The molecular effect of glucagon‐like peptide 1 receptor (GLP‐1R) agonism on the kidneys in diabetic kidney disease is not widely known. Hence, we used mass spectrometry‐based proteomics to investigate the influence of GLP‐1R agonism on protein abundances in the kidneys of streptozotocin (STZ)‐induced diabetic mice. Several abundances were altered, mainly revealing proteins with structural function or involved in stress responses.

The GLP‐1 receptor (GLP‐1R) in the kidney is expressed exclusively in vascular smooth muscle cells in arteries and arterioles. Downstream effects of the activation of the renal vascular GLP‐1R are elusive but may involve regulation of the renin‐angiotensin‐aldosterone system (RAAS). The expression of Ren1 in the mouse renal vasculature was investigated by in situ hybridization after a single subcutaneous dose of liraglutide, semaglutide and after repeated injections of liraglutide. Single and repeated exposure to GLP‐1R agonists induced expression of Ren1 in the renal vascular smooth muscle cell compartment compared with vehicle injected controls (p < .0001) for both semaglutide and liraglutide. The present data show a robust induction of Ren1 expression in the vascular smooth muscle cells of the kidney after single and repeated GLP‐1R activation and this renin recruitment may be involved in the effects of GLP‐1R agonist treatment on kidney disease. Single and repeated injections with long acting GLP‐1R agonists leads to induction of Ren1 transcription from VSMC in renal vasculature in mice.

Diabetes mellitus (DM) is a worldwide disease that affects 9% of the adult world population and type 2 DM accounts for 90% of those. A common consequence of DM is kidney complications, which could lead to kidney failure. We studied the potential effects of treatment with insulin and the glucagon‐like peptide 1 receptor (GLP‐1R) agonist liraglutide on the diabetic kidney proteome through the use of the db/db mouse model system and mass spectrometry (MS). Multivariate analyses revealed distinct effects of insulin and liraglutide on the db/db kidney proteome, which was seen on the protein levels of, for example, pterin‐4 α‐carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor‐1α (PCBD1), neural precursor cell expressed developmentally down‐regulated‐8 (NEDD8), transcription elongation factor‐B polypeptide‐1 (ELOC) and hepcidin (HEPC). Furthermore, the separation of the insulin, liraglutide and vehicle db/db mouse groups in multivariate analyses was not mainly related to the albumin excretion rate (AER) or the level of glycated hemoglobin A1c (HbA1c%) in the mice. In summary, we show that insulin and liraglutide give rise to separate protein profiles in the db/db mouse kidney. Insulin and the glucagon‐like peptide 1 receptor agonist liraglutide, both used in the treatment of type 2 diabetes mellitus, are here shown to have distinct effects on the kidney proteome in db/db mice. These effects do not seem to correlate with blood glucose levels, glycated hemoglobin A1c or albuminuria, which could suggest direct receptor‐mediated effects of the treatments on the kidney proteome.

We assessed the efficacy of simultaneous agonism at the glucagon‐like peptide‐1 receptor (GLP‐1R) and the melanocortin‐4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet‐induced obese (DIO) mice were chronically treated with either the long‐acting GLP‐1R agonist liraglutide, the MC4R agonist RM‐493 or a combination of RM‐493 and liraglutide. Co‐treatment of DIO mice with RM‐493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono‐therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM‐493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp‐1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM‐493 enhanced hypothalamic Mc4r expression. Hence, co‐dosing with MC4R and GLP‐1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP‐1R agonism for the treatment of obesity and diabetes. Synopsis Combination therapy with a melanocortin‐4 receptor agonist (RM‐493) and a GLP‐1 receptor agonist (liraglutide) potently reversed obesity, dyslipidemia and glucose metabolic perturbations in diet‐induced obese mice chronically maintained on a high‐fat, high‐sugar diet. RM‐493 and liraglutide co‐treatment amplifies weight loss and improves glucose and lipid metabolism beyond that of either compound used as a mono‐therapy. MC4R‐agonism enhances GLP‐1R signaling in the hypothalamus. Dual MC4R and GLP‐1R agonism improves insulin signaling and cholesterol metabolism in the liver. This poly‐pharmacological treatment holds promise as a novel opportunity for treating diet‐induced metabolic disorders. Graphical Abstract Combination therapy with a melanocortin‐4 receptor agonist (RM‐493) and a GLP‐1 receptor agonist (liraglutide) potently reversed obesity, dyslipidemia and glucose metabolic perturbations in diet‐induced obese mice chronically maintained on a high‐fat, high‐sugar diet.