Biology subjects

Spaas, J.

Publications and source records attributed to Spaas, J..

8 recordsLinked to original sources

bioRxiv2026

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

physiology↗

bioRxiv2026

A small molecule PTER-selective inhibitor reduces food intake and body weight

PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic taurine metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remain unknown, limiting our ability to harness this pathway therapeutically. Here we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a first-in-class substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. Administration of PTERi to diet-induced obese mice reduces feeding, enhances GLP1-RA (glucagon like peptide 1 receptor agonist)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for pharmacological inhibition of PTER in obesity.

biochemistry↗

bioRxiv2026

Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway

Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1-3. Using untargeted metabolomics, here we show that circulating levels of the metabolite para-tyramine-O-sulfate (pTOS) are increased >1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulfation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.

physiology↗

bioRxiv2025

N-acetylcarnosine attenuates age-associated declines in multi-organ systems to improve survival

Histidine containing dipeptides (HCDs) such as N-acetylcarnosine are endogenous metabolites that are ergogenic and mitigate metabolic dysfunction. We previously demonstrated that short-term N-acetylcarnosine treatment is highly efficacious in protecting muscle atrophy induced by disuse. Here we demonstrate that a 6-months treatment of N-acetylcarnosine attenuates a broad spectrum of age-associated maladies and improved survival by [~]50% in female mice. A comprehensive survey of organ systems revealed that N-acetylcarnosine prevents decline in adiposity, diastolic function, vasodilation, muscle strength, and bone density. Together, N-acetylcarnosine substantially delays the onset of system-wide end-stage pathology to prolong lifespan. As an endogenously present metabolite, treatment with N-acetylcarnosine may be a safe and promising intervention to promote healthy aging in humans.

physiology↗

bioRxiv2024

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance

{beta}-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

biochemistry↗

bioRxiv2024

SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans

N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are also increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating that urine and plasma Lac-Phe pools are functionally and biochemically de-coupled. Together, these data establish SLC17 family members as the physiologic urine transporters for Lac-Phe and uncover a biochemical pathway for the renal excretion of this signaling metabolite.

biochemistry↗

bioRxiv2023

Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immune-modulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, the presence of CARNS1 and endogenous HCDs does not protect against cuprizone-induced demyelination, and is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur. Exogenously administered carnosine is not effective in blunting demyelination or accelerating remyelination. In conclusion, we show that CARNS1 is diminished in demyelinated MS lesions, which may have detrimental effects on disease progression through weakening the endogenous protection against neuroinflammation.

neuroscience↗

bioRxiv2023

Extensive profiling of histidine-containing dipeptides reveals species-specific distribution and metabolism in mice, rats and humans

Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules linked to inflammatory, metabolic and neurological diseases, as well as exercise performance. Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n=26, n=25, n=19 tissues, respectively). Our data show that tissue HCD levels are uniquely regulated by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibers and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analog N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion. Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease. Significance statementBy extensively profiling the pluripotent histidine-containing dipeptides across three species, we generated many new insights into species- and tissue-specific histidine-containing dipeptide metabolism. For instance, the only stable analog that is specific for the human circulation (N-acetylcarnosine) is continuously released from muscle tissue and is positively regulated by physical exercise. The great number of analyses and experiments involving humans establishes great translational value of the findings. These new data open exciting opportunities to study histidine-containing dipeptide metabolism, including paracrine and/or endocrine signaling of these dipeptides, possibly contributing to the potent health-promoting exercise effects.

physiology↗