Cover Story Current Issue

Altered amino acid metabolism is increasingly appreciated as a key driver in the pathology of multiple diseases, including metabolic syndrome, cancer, and neurological disease. Sphingolipids (SLs) are synthesized from serine and fatty acyl-CoAs by serine palmitoyltransferase (SPT) and are critical signaling molecules and membrane components that are enriched in the nervous system and retina. When serine levels are low, alanine (or glycine) is used as a substrate by SPT to yield non-canonical 1-deoxysphingolipids (doxSLs) that drive neuropathy and cellular dysfunction through diverse mechanisms. This highlights a potential mechanism for crosstalk between amino acid metabolism and SL biosynthesis in the context of neurological dysfunction. Numerous heritable neurological and retinal disorders are causative or linked to mutations in genes encoding SL-metabolizing enzymes, including amyotrophic lateral sclerosis (ALS), Tay-Sachs, Niemann-Pick disease, Gaucher disease, Macular telangiectasia type II (MacTel), and hereditary sensory and autonomic neuropathy type 1 (HSAN1).

Courtney R. Green, Roberto Bonelli, Brendan R.E. Ansell, Simone Tzaridis, ... Marin L. Gantner

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Current Issue

Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release

Michael P. Greenwood, Mingkwan Greenwood, Soledad Bárez-López, Joe W. Hawkins, ... David Murphy

Objectives

The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release.

Methods

We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland.

Results

We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis.

Conclusion

In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

 

Articles in Press

Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release

Michael P. Greenwood, Mingkwan Greenwood, Soledad Bárez-López, Joe W. Hawkins, ... David Murphy

Objectives

The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release.

Methods

We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland.

Results

We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis.

Conclusion

In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

 

2021 impact factor: 8.568

You are what you eat

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