Biology subjects

Rosen, C. J.

Publications and source records attributed to Rosen, C. J..

15 recordsLinked to original sources

bioRxiv2025

In C57Bl6 Mice, Obesity and Subsequent Weight Loss Negatively Affected the Skeleton and Shifted the Cortical Bone Metabolome

Obesity and calorie restriction each negatively affect skeletal health. Despite the negative effects of weight loss on the skeleton, obese patients are advised to lose weight via calorie restriction. Additionally, obesity and weight loss individually alter both whole-body and local metabolism. Little is known about bone quality and changes to the cortical metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would worsen bone quality in obese mice by shifting the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL6/J mice received 60% high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30% caloric restriction. Control animals received a 10% low-fat diet. Bodyweight and fat mass were increased by obesity and decreased with calorie restriction. Similarly, glucose and insulin tolerance were worsened with obesity but improved by weight loss. Compared to obesity, calorie restriction elicited more bone loss in both cortical and trabecular compartments. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. Our findings highlight the negative effects of obesity and subsequent caloric restriction on the skeleton. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models did not restore bone morphology or the cortical metabolome to control conditions.

cell biology↗

bioRxiv2025

Compost amendments to potato soils enrich yield-associated members of soil microbiomes across the continental US

Plant health is regulated by complex consortia of soil microbes with growth-promoting and pathogenic functions. In potato production, various soil management practices are undertaken to boost yields and suppress diseases, but connections between these practices, soil microbiomes, and tuber yields have not been characterized across diverse growing regions. To identify growing practices and microbes associated with increased yields, we established four-year field trials across eight US sites from Oregon to Maine that consisted of controls, fumigations, organic amendments, and mustard incorporations. Soil microbiomes consisted of 16S and ITS amplicon sequences from bacteria and microeukaryotes, respectively. While soil treatments influenced microbiomes differently across all field sites, eukaryotes were more sensitive than bacteria to all treatments. Soil treatments impacted proportions of distinct amplicon sequence variants (ASVs), and associations between ASVs and tuber yields varied within genus-level taxonomy and across field sites. Forty-five ASVs were identified as both treatment-impacted and yield-associated within any field site. Models identified three of thirteen compost amendment scenarios and one of thirteen fumigation scenarios that increased tuber yields by increasing proportions of these taxa within soil microbiomes. These ASVs were not influenced by treatment-associated changes in soil nutrients or organic matter, highlighting complex relationships within specific field sites that require further study to achieve the goal of implementing sustainable, microbiome-informed potato production techniques. ImportanceSoil microbes play diverse and interconnected roles in mediating plant health, growth, and disease, but understanding the specifics of how they work and applying them across different agricultural systems remains a challenge. To address this, we amassed a dataset from eight potato field sites across major US growing regions consisting of nearly two thousand soil bacterial and fungal microbiomes paired with soil chemical and tuber yield data. We describe how soil microbiomes are impacted by different soil treatments (compost amendments, chemical fumigation, and mustard incorporation), and identify treatments that boosted yields by up to 23% by increasing proportions of certain bacterial or fungal sequences. Compost amendments affected yield-associated taxa more often than other soil treatments, but these effects varied by rotation length and growing region. Changes to soil chemistry resulting from specific soil treatments did not influence abundances of yield-associated taxa, suggesting that the ways in which they may act to maintain plant vigor are field-specific and complex, calling for further study.

microbiology↗

bioRxiv2024

PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation

ObjectiveThe skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels. MethodsIn vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1CrePpar{gamma}flfl male and female mice ({gamma}OTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Ppar{gamma}. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. ResultsCirculating sclerostin levels of {gamma}OTKO male and female mice were not different from control mice. Male {gamma}OTKO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from {gamma}OTKO males suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS). ConclusionsPPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism. HighlightsO_LIOsteocytes function as a body energostat via their bioenergetics C_LIO_LIPPARG protein acts as a "molecular break" of osteocyte mitochondrial activity C_LIO_LIPPARG deficiency activates TCA cycle, oxidative stress and ROS accumulation C_LIO_LIPPARG controls osteocyte insulin signaling and fuel utilization C_LI

physiology↗

bioRxiv2023

Transcriptomic network analysis of brain and bone reveals shared molecular mechanisms underlyingAlzheimer's Disease and related dementias and Osteoporosis

Alzheimers disease and related dementias (ADRD) and Osteoporosis (OP) are two prevalent diseases of aging with numerous epidemiological associations, but the underlying molecular mechanisms contributing to this association are unknown. We used WGCNA (weighted gene co-expression network analysis) to develop transcriptomic networks in bone and brain tissue using two different studies to discover common molecular mechanisms. We used RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Memory and Aging Project), including a subset of 298 meeting criteria for inclusion in five ADRD categories and the full set in a secondary analysis, and RNA array data from transiliac bone in 84 participants from the Oslo study of postmenopausal women. After developing each network, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks, most notably among those modules linked to canonical Wnt signaling and skeletal tissue homeostasis and development. These results were preserved with a network from the full ROSMAP cohort (n=629), which included a broader spectrum of participants. Our results require validation in experimental studies but show support for Wnt signaling as an important driver of pathology in OP and ADRD. We additionally show a strong link between Dementia with Lewy bodies and bone outcomes. These results have translational significance in the development of novel treatments and biomarkers for both ADRD and OP.

neuroscience↗

bioRxiv2023

Development and Biophysical Characterization of a Humanized FSH-Blocking Monoclonal Antibody Therapeutic Formulated at an Ultra-High Concentration

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the creation of a unique formulation for our first-in- class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimers disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulations long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, conformed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) spectroscopy. Three rapid freeze-thaw cycles at -80{degrees}C/25{degrees}C or -80{degrees}C/37{degrees}C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4{degrees}C and 25{degrees}C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80{degrees}C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

bioengineering↗

bioRxiv2022

Evaluation of a scalable approach to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells

Genome-wide association studies (GWASs) have revolutionized our understanding of the genetics of complex diseases, such as osteoporosis; however, the challenge has been converting associations to causal genes. Studies have demonstrated the utility of transcriptomics data in linking disease-associated variants to genes; though for osteoporosis, few population transcriptomics datasets have been generated on bone or bone cells, and an even smaller number have profiled individual cell-types. To begin to evaluate approaches to address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions, a popular model of osteoblast differentiation and activity, from five Diversity Outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model for the generation of cell-type specific transcriptomic profiles of mesenchymal lineage cells derived from large populations of mice to inform genetic studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were nearly identical from a transcriptomic perspective to cells isolated directly from bone. We also demonstrated the ability to multiplex single cells and subsequently assign cells to their "mouse-of-origin" using demultiplexing approaches based on genotypes inferred from coding SNPs. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell-types. SCENIC was used to reconstruct gene regulatory networks (GRNs) and we showed that identified cell-types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of BMD heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically informative model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells in large mouse, and potentially human, populations.

bioinformatics↗

bioRxiv2022

PTH regulates osteogenesis and suppresses adipogenesis through Zfp 467 in a feed-forward, cyclic AMP-dependent manner

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate towards osteogenesis and higher bone mass. In this study we hypothesized that PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass. We report that PrrxCre Zfp467 but not AdipoCre Zfp467 mice exhibit an identical phenotype to the Zfp467-/-mice with high bone mass and greater osteogenic differentiation We also found that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of p50 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467 -/-calvarial osteoblasts, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via p50 and thus cellular responsiveness to PTH, ultimately leading to enhanced bone formation.

cell biology↗

bioRxiv2022

Creating an atlas of the bone microenvironment during oral inflammatory-related bone disease using single-cell profiling

Oral inflammatory diseases such as apical periodontitis are common bacterial infectious diseases that may affect the periapical alveolar bone tissues. A protective healing process occurs simultaneously with the inflammatory tissue destruction, in which mesenchymal stem cells (MSCs) play a primary role. However, a systematic and precise description of the cellular and molecular composition of the microenvironment of bone affected by inflammation is lacking. In this study, we created a single cell atlas of cell populations that compose alveolar bone in healthy and inflammatory disease states. We investigated changes in expression frequency and patterns related to apical periodontitis, as well as the interactions between MSCs and immunocytes. Our results highlight an enhanced self-supporting network and osteogenic potential within MSCs during apical periodontitis-associated inflammation. MSCs not only differentiated towards osteoblast lineage cells, but also expressed higher levels of osteogenic related markers, including SPARC and Col11. This was confirmed by lineage tracing in transgenic mouse models and human samples from oral inflammatory-related alveolar bone lesions. In summary, the current study provides an in-depth description of the microenvironment of MSCs and immunocytes in both healthy and disease states. We also identified key apical periodontitis-associated MSC subclusters and their biomarkers, which could further our understanding of the healing process and the underlying mechanisms of oral inflammatory-related bone disease. Taken together, these results enhance our understanding of heterogeneity and cellular interactions of alveolar bone cells under pathogenic and inflammatory conditions. We provide these data as a tool for investigators not only to better appreciate the repertoire of progenitors that are stress responsive but importantly to help design new therapeutic targets to restore bone lesions caused by apical periodontitis and other inflammatory-related bone diseases.

cell biology↗

bioRxiv2022

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHRs, LHCGRs and FSHRs. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub-nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub-nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHRs in human brain samples, where transcripts were co-localized in MALAT1-positive neurons. In addition, we show high expression for all three receptors in the ventricular region--with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. TSHRs were expressed specifically in tanycytes. In contrast, Fshrs were localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain--both are Alzheimers disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

neuroscience↗

bioRxiv2022

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.

cell biology↗

bioRxiv2021

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

BackgroundBone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. MethodsUsing C57BL/6 mice as a model, we employed the bone-protected PPAR{gamma} constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a CT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers. ResultsWe have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPAR{gamma} acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/{beta}- catenin signaling. ConclusionsAdipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. FundingThis work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).

molecular biology↗

bioRxiv2021

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.

physiology↗

bioRxiv2020

Systems genetics analyses in Diversity Outbred mice inform human bone mineral density GWAS and identify Qsox1 as a novel determinant of bone strength

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we used Diversity Outbred (DO) mice to directly address these limitations by performing the first systems genetics analysis of 55 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 72 genes likely to be causal for human BMD GWAS associations, including the novel genes SERTAD4 and GLT8D2. We also performed GWAS in the DO for a wide-range of bone traits and identified Qsox1 as a novel gene influencing cortical bone accrual and bone strength. Our results provide a new perspective on the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

genetics↗

bioRxiv2020

Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo

The myokine irisin facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In the current study we investigated whether irisin also directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J bone marrow progenitors; this increase was blocked by a neutralizing antibody to integrin V{beta}5. Irisin also increased resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating clastokines. In vivo, forced expression of the irisin precursor Fndc5 in murine muscle resulted in low bone mass and increased number of osteoclasts. Taken together, our work demonstrates that irisin acts directly on cultured osteoclast progenitors to increase differentiation and promote bone resorption. These actions support the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone during exercise.

cell biology↗

bioRxiv2020

PHOSPHO1, a novel skeletal regulator of insulin resistance and obesity

The skeleton is recognised as a key endocrine regulator of metabolism. Here we show that mice lacking the bone mineralization enzyme PHOSPHO1 (Phospho1-/-) exhibited improved basal glucose homeostasis and resisted high-fat-diet induced weight gain and diabetes. The metabolic protection in Phospho1-/- mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1-/- mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1-/- mice. However, the decreased serum choline levels in Phospho1-/- mice were normalized by feeding a 2% choline rich diet resulting in a normalization in insulin sensitivity and fat mass. This study identifies PHOSPHO1 as a potential therapeutic target for the treatment of obesity and diabetes.

physiology↗