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BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

ABSTRACT: BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

PROVIDER: PRJNA868929 | ENA |

REPOSITORIES: ENA

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BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

Project description:Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism.

2022-12-09 | GSE211105 | GEO

Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

Project description:Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

2024-06-11 | GSE243681 | GEO

Dietary protein defends lean mass and maintains metabolic benefits of glucagon receptor agonist G108 in mice

Project description:Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained in contexts that permit the defence of lean mass.

2024-09-09 | GSE273658 | GEO

Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

Project description:Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

| PRJNA1019376 | ENA

Generalized reversal of glial and neurovascular cell transcriptomic aging signatures by glucagon-like peptide-1 receptor agonist

Project description:Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Recently, we demonstrated that brain endothelial cell (EC) aging is transcriptomically and functionally reversible by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA)(1). Here, we report that the reversal of transcriptomic aging signatures by GLP-1RA treatment is a generalized phenomenon in multiple major brain cell types, including glial (including astrocyte (AC), oligodendrocyte precursor cell (OPC), microglia (MG) and oligodendrocyte (OLG)) and mural (i.e. pericyte (PC) and smooth muscle cell (SMC)) cells. The age-related expression changes ameliorated by GLP-1RA encompass cell type-shared and specific functional pathways implicated in aging and neurodegeneration. These results show the feasibility of brain ageing reversal by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients(2, 3), and imply that GLP-1RA may be a generally applicable pharmacological intervention for non-diabetic patients at risk of age-related neurodegeneration.

2021-01-31 | GSE160991 | GEO

Differential effects of a glucagon-like peptide 1 receptor agonist in NAFLD and in response to hepatectomy

Project description:Differential effects of a glucagon-like peptide 1 receptor agonist in NAFLD and in response to hepatectomy

| PRJNA490142 | ENA

Generalized reversal of glial and neurovascular cell transcriptomic aging signatures by glucagon-like peptide-1 receptor agonist

Project description:Generalized reversal of glial and neurovascular cell transcriptomic aging signatures by glucagon-like peptide-1 receptor agonist

| PRJNA675086 | ENA

Glucagon-like peptide-1 suppresses sympathetic activation via peripheral chemosensory inhibition

Project description:Glucagon-like peptide-1 suppresses sympathetic activation via peripheral chemosensory inhibition

| PRJNA739448 | ENA

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Project description:Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight-loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding, likely in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

2024-10-07 | GSE277578 | GEO

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Project description:Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

| PRJNA1162854 | ENA