Biology subjects

Svensson, K. J.

Publications and source records attributed to Svensson, K. J..

16 recordsLinked to original sources

bioRxiv2026

Restoration of Capacity to Build Muscle Strength in Geriatric Mice by Inhibition of the Gerozyme 15-Prostaglandin Dehydrogenase

Loss of skeletal muscle mass and strength with age drives sarcopenia, a syndrome affecting >100 million people worldwide that leads to loss of mobility, independence, and increased mortality. Mechanical overload induces hypertrophy in young muscle, but this response is markedly attenuated with age--a poorly understood phenomenon termed "anabolic resistance." Here we test whether impaired paracrine communication between myofibers and their niche underlies this loss of plasticity in geriatric mice. In aged muscle, pharmacological inhibition of 15-PGDH restores prostaglandin E2 (PGE2) bioavailability and rescues the anabolic response, increasing muscle growth and contractile strength. Single-nuclei RNA-seq revealed a paracrine circuit: PGE2 drives IGF1 synthesis in type IIb myonuclei, which signals to stromal, myogenic, myonuclear, and immune cells. Blocking IGF1 receptor signaling abolished these gains, placing PGE2 upstream of an IGF1-mediated circuit that coordinates multicellular hypertrophy. Thus, 15-PGDH inhibition is a pharmacological strategy to overcome the anabolic resistance and rebuild muscle in aging.

cell biology↗

bioRxiv2026

ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance

The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has long been linked with metabolic diseases, with the common ENPP1 K173Q (historically K121Q) variant conferring increased risk for type 2 diabetes (T2D). However, the mechanistic basis of this association has remained unclear. Here, we demonstrate that the K173Q variant has decreased cGAMP hydrolysis activity, suggesting that this loss of enzymatic function could contribute to its pathogenesis. Using a cGAMP-hydrolysis-deficient knock-in mouse (Enpp1H362A), we show that selective loss of this activity leads to a primary defect in energy expenditure and exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An unbiased in vivo glucose-uptake screen reveals brown adipose tissue (BAT) as a focal site of metabolic impairment, characterized by profound extracellular cGAMP accumulation and a selective failure of insulin-stimulated glucose uptake. Mechanistically, we demonstrate that nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP production and export. Excess cGAMP directly propagates STING-dependent suppression of glucose uptake and lipogenesis in brown adipocytes. Additionally, when ENPP1-mediated clearance is compromised, extracellular cGAMP acts as a paracrine immunotransmitter that remodels the BAT microenvironment by recruiting and polarizing macrophages toward an M1-like phenotype. Together, our findings nominate the impaired ENPP1-dependent buffering of extracellular cGAMP as one mechanism by which ENPP1 variants influence metabolic homeostasis.

immunology↗

bioRxiv2026

15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.

cell biology↗

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↗

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

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1+/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1+/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

physiology↗

bioRxiv2024

A PTER-dependent pathway of taurine metabolism linked to energy balance

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

biochemistry↗

bioRxiv2024

Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma

Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.

cancer biology↗

bioRxiv2023

A class of secreted mammalian peptides with potential to expand cell-cell communication

Peptide hormones and neuropeptides are fundamental signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we demonstrate the endogenous presence of a sequence diverse class of orphan, blood-borne peptides that we call "capped peptides." Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications - N-terminal pyroglutamylation and C-terminal amidation - which function as chemical "caps" of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic regulation in blood plasma by diverse environmental and physiologic stimuli. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of multiple mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide that reduces food intake and body weight. Capped peptides therefore define a largely unexplored class of circulating molecules with potential to regulate cell-cell communication in mammalian physiology.

physiology↗

bioRxiv2023

Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold

Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying novel ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold as a screening approach to identify extracellular ligand-binding pairs using a structural library of single-pass transmembrane receptors. Key to the approach is the optimization of AlphaFold input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions. Importantly, the predictions were performed on ligand-receptor pairs not used for AlphaFold training. We demonstrate high discriminatory power and a success rate of close to 90 % for known ligand-receptor pairs and 50 % for a diverse set of experimentally validated interactions. These results demonstrate proof-of-concept of a rapid and accurate screening platform to predict high-confidence cell-surface receptors for a diverse set of ligands by structural binding prediction, with potentially wide applicability for the understanding of cell-cell communication.

biochemistry↗

bioRxiv2022

Organism-wide secretome mapping uncovers pathways of tissue crosstalk in exercise

There has been growing interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell type-specific proteomic approach to generate a 21-cell type, 10-tissue map of exercise-regulated secretomes in mice. Our dataset identifies >200 exercise-regulated cell type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Elevated lactate levels can directly regulate protein secretion. Lastly, we establish an anti-obesity and anti-diabetic role for a proteoform of an intracellular carboxylesterase whose secretion from the liver is induced by exercise training. Together, our data uncover the dynamic remodeling of cell and tissue crosstalk by physical activity.

systems biology↗

bioRxiv2022

Single-cell analysis of non-alcoholic fatty livers identifies a role for the constitutive androstane receptor

Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. While several genetic risk factors have been identified, the cellular and molecular heterogeneity associated with the development of hepatic steatosis are still not fully understood. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic nonparenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression with unique molecular signatures of lipid synthesis. We find that NAFLD livers have elevated expression of the constitutive androstane receptor (CAR), a gene previously associated with lipid synthesis. Furthermore, nuclear expression of CAR positively correlates with steatohepatitis in humans. These findings demonstrate significant cellular differences in lipid signatures and identify a gene with a high likelihood of being linked to hepatic steatosis in humans.

cell biology↗

bioRxiv2022

CROP-Seq: a single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes

ObjectiveCROP-Seq combines gene silencing using CRISPR interference (CRISPRi) with single-cell RNA sequencing (scRNA-Seq) to conduct a functional reverse genetic screen of novel gene targets associated with adipocyte differentiation or function, with single-cell transcriptomes as the readout. MethodsWe created a human preadipocyte SGBS cell line with stable expression of KRAB-dCas9 for CRISPRi-mediated gene knock-down. This line was transduced with a lentiviral library of sgRNAs targeting 6 genes of interest (3 sgRNAs / gene, 18 sgRNAs), 6 positive control genes (3 sgRNAs / gene, 18 sgRNAs), and non-targeting control sgRNAs (4 sgRNAs). Transduced cells were selected and differentiated, and individual cells were captured using microfluidics at day 0, 4 and 8 of adipogenic differentiation. Next, expression and sgRNA libraries were created and sequenced. Bioinformatic analysis of resulting scRNA-Seq expression data was used to determine the effects of gene knock-down and the dysregulated pathways, and to predict cellular phenotypes. ResultsSingle-cell transcriptomes obtained from SGBS cells following CRISPRi recapitulate different states of differentiation from preadipocytes to adipocytes. We confirmed successful knock-down of targeted genes. Transcriptome-wide changes were observed for all targeted genes, with over 400 differentially expressed genes identified per gene at least at one timepoint. Knock-down of known adipogenesis regulators PPARG and CEBPB inhibited adipogenesis. Gene set enrichment analyses revealed molecular processes for adipose tissue differentiation and function for novel genes. MAFF knock-down led to a downregulation of transcriptional response to proinflammatory cytokine TNF- in preadipocytes. TIPARP knock-down resulted in an increase in the expression of a beiging marker UCP1 at D8 of adipogenesis. ConclusionsThe CROP-Seq system in SGBS cells can determine the consequences of target gene knock-down at the transcriptome level. This powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte and adipocyte function associated with metabolic disease. HighlightsO_LICRISPR interference screen coupled with single-cell RNA sequencing (CROP-Seq) C_LIO_LIParallel screening of 12 genes in human SGBS adipocytes and preadipocytes C_LIO_LIUncovered novel regulators of adipogenesis and adipocyte function C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/497796v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ee34b6org.highwire.dtl.DTLVardef@1c6ba8aorg.highwire.dtl.DTLVardef@fa89org.highwire.dtl.DTLVardef@403966_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes (T2D). Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for T2D, but the mechanism behind this association has remained elusive. Here for the first time we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. Our findings establish a previously unknown role of Gpr151 in the liver and provides an explanation to the lowered T2D risk in individuals with nonsynonymous mutations in GPR151. This study highlights the therapeutic potential of targeting GPR151 for treatment of metabolic disease.

physiology↗

bioRxiv2022

Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1

The secreted protein Isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53 % overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in [~] 450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this anti-diabetic circulating protein controls muscle biology.

cell biology↗

bioRxiv2020

A CRISPR-based genome-wide screen for adipogenesis reveals new insights into mitotic expansion and lipogenesis.

In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and by upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional genomics screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. The pooled screening strategy utilized FACS to isolate populations based on lipid content by gating for fluorescence intensity of the lipophilic, green fluorescent BODIPY dye. Additionally, the approach categorized if genes functioned during mitotic expansion or lipogenesis. Cellular mechanisms regulating the rate of protein translation and protein stability were found critical for adipogenesis and lipogenesis. These protein-directed mechanisms were further supported by proteomic analyses, which demonstrated that essential changes in protein abundance driving 3T3-L1 adipogenesis were not driven by transcription. We exemplify this theme by showing that the hypusination pathway, a conserved regulator of translation initiation, is critical to translate adipogenic inducers of mitotic expansion and that the neddylation/ubiquitin pathway modulates insulin sensitivity to regulate lipogenesis.

molecular biology↗