Reconstructing the landscape of gut microbial species across 29,000 diverse individuals.

The human gut microbiome has been linked to health and disease. Investigation of the human microbiome has largely employed 16S amplicon sequencing, with limited ability to distinguish microbes at the species level. Herein, we describe the development of Reference-based Exact Mapping (RExMap) of microbial amplicon variants that enables mapping of microbial species from standard 16S sequencing data. RExMap analysis of 16S data captures ∼75% of microbial species identified by whole-genome shotgun sequencing, despite hundreds-fold less sequencing depth. RExMap re-analysis of existing 16S data from 29,349 individuals across 16 regions from around the world reveals a detailed landscape of gut microbial species across populations and geography. Moreover, RExMap identifies a core set of fifteen gut microbes shared by humans. Core microbes are established soon after birth and closely associate with BMI across multiple independent studies. RExMap and the human microbiome dataset are presented as resources with which to explore the role of the human microbiome.

A Retrospective Analysis of Medical Student Performance Evaluations, 2014-2020: Recommend with Reservations.

BACKGROUND: The Medical Student Performance Evaluations (MSPE) is a cornerstone of residency applications. Little is known regarding adherence to Association of American Medical Colleges (AAMC) MSPE recommendations and longitudinal changes in MSPE content. OBJECTIVES: Evaluate current MSPE quality and longitudinal changes in MSPE and grading practices. DESIGN: Retrospective analysis. PARTICIPANTS: Students from all Liaison Committee on Medical Education (LCME)-accredited medical schools from which the Stanford University Internal Medicine residency program received applications between 2014-2015 and 2019-2020. MAIN MEASURES: Inclusion of key words to describe applicant performance and metrics thereof, including distribution among students and key word assignment explanation; inclusion of clerkship grades, grade distributions, and grade composition; and evidence of grade inflation over time. KEY RESULTS: MSPE comprehensiveness varied substantially among the 149 schools analyzed. In total, 25% of schools provided complete information consistent with AAMC recommendations regarding key word/categorization of medical students and clerkship grades in 2019-2020. Seventy-seven distinct key word terms appeared across the 139 schools examined in 2019-2020. Grading practices markedly varied, with 2-83% of students receiving the top internal medicine clerkship grade depending on the year and school. Individual schools frequently changed key word and grading practices, with 33% and 18% of schools starting and/or stopping use of key words and grades, respectively. Significant grade inflation occurred over the 6-year study period, with an average 14% relative increase in the proportion of students receiving top clerkship grades. CONCLUSIONS: A minority of schools complies with AAMC MSPE guidelines, and MSPEs are inconsistent across time and schools. These practices may impair evaluation of students within and between schools.

Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects.

OBJECTIVE: Retinoic acid (RA) is a ligand for nuclear receptors that modulate gene transcription and cell differentiation. Whether RA controls ectopic calcification in humans is unknown. We tested the hypothesis that RA regulates osteogenic differentiation of human arterial smooth muscle cells and aortic valvular interstitial cells that participate in atherosclerosis and heart valve disease, respectively. Approach and Results: Human cardiovascular tissue contains immunoreactive RAR (RA receptor)-a retinoid-activated nuclear receptor directing multiple transcriptional programs. RA stimulation suppressed primary human cardiovascular cell calcification while treatment with the RAR inhibitor AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in a coordinated manner, increasing levels of the calcification inhibitor MGP (matrix Gla protein) while decreasing calcification-promoting TNAP (tissue nonspecific alkaline phosphatase) activity. Given that nuclear receptor action varies as a function of distinct ligand structures, we compared calcification responses to cyclic retinoids and the acyclic retinoid peretinoin. Peretinoin suppressed human cardiovascular cell calcification without inducing either secretion of APOC3 (apolipoprotein-CIII), which promotes atherogenesis, or reducing CYP7A1 (cytochrome P450 family 7 subfamily A member 1) expression, which occurred with cyclic retinoids all-trans RA, 9-cis RA, and 13-cis RA. Additionally, peretinoin did not suppress human femur osteoblast mineralization, whereas all-trans RA inhibited osteoblast mineralization. CONCLUSIONS: These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids.

Generation of induced pluripotent stem cell lines from South Asian ethnicity.

South Asians, which represent around 25% of the world's population, have a disproportionately high risk of cardiometabolic disease, two-fold higher risk of myocardial infarction, and 4- to 6-fold higher risk for diabetes compared to Caucasians. We generated two induced pluripotent stem cell (iPSC) lines from healthy South Asian donors and validated the pluripotency and ability of these cell lines to differentiate into three germ layers. These iPSC lines can be applied to generate many cardiovascular cell types such as cardiomyocytes, endothelial cells, and mural cells to investigate different cardiovascular disease mechanisms triggered by environmental risk factors or drugs in vitro.

Predicting clinical outcomes of SARS-CoV-2 infection during the Omicron wave using machine learning.

The Omicron SARS-CoV-2 variant continues to strain healthcare systems. Developing tools that facilitate the identification of patients at highest risk of adverse outcomes is a priority. The study objectives are to develop population-scale predictive models that: 1) identify predictors of adverse outcomes with Omicron surge SARS-CoV-2 infections, and 2) predict the impact of prioritized vaccination of high-risk groups for said outcome. We prepared a retrospective longitudinal observational study of a national cohort of 172,814 patients in the U.S. Veteran Health Administration who tested positive for SARS-CoV-2 from January 15 to August 15, 2022. We utilized sociodemographic characteristics, comorbidities, and vaccination status, at time of testing positive for SARS-CoV-2 to predict hospitalization, escalation of care (high-flow oxygen, mechanical ventilation, vasopressor use, dialysis, or extracorporeal membrane oxygenation), and death within 30 days. Machine learning models demonstrated that advanced age, high comorbidity burden, lower body mass index, unvaccinated status, and oral anticoagulant use were the important predictors of hospitalization and escalation of care. Similar factors predicted death. However, anticoagulant use did not predict mortality risk. The all-cause death model showed the highest discrimination (Area Under the Curve (AUC) = 0.903, 95% Confidence Interval (CI): 0.895, 0.911) followed by hospitalization (AUC = 0.822, CI: 0.818, 0.826), then escalation of care (AUC = 0.793, CI: 0.784, 0.805). Assuming a vaccine efficacy range of 70.8 to 78.7%, our simulations projected that targeted prevention in the highest risk group may have reduced 30-day hospitalization and death in more than 2 of 5 unvaccinated patients.

Temporal trends in lipoprotein(a) testing among United States veterans from 2014 to 2023.

Objective: Lipoprotein (a) [Lp(a)] is a causal, genetically-inherited risk amplifier for atherosclerotic cardiovascular disease (ASCVD). Practice guidelines increasingly recommend broad Lp(a) screening among various populations to optimize preventive care. Corresponding changes in testing rates and population-level detection of elevated Lp(a) in recent years has not been well described. Methods: Using Veterans Affairs electronic health record data, we performed a retrospective cohort study evaluating temporal trends in Lp(a) testing and detection of elevated Lp(a) levels (defined as greater than 50 mg/dL) from January 1, 2014 to December 31, 2023 among United States Veterans without prior Lp(a) testing. Testing rates were stratified based on demographic and clinical factors to investigate possible drivers for and disparities in testing: age, sex, race and ethnicity, history of ASCVD, and neighborhood social vulnerability. Results: Lp(a) testing increased nationally from 1 test per 10,000 eligible Veterans (558 tests) in 2014 to 9 tests per 10,000 (4,440 tests) in 2023, while the proportion of elevated Lp(a) levels remained stable. Factors associated with higher likelihood of Lp(a) testing over time were a history of ASCVD, Asian race, and residing in neighborhoods with less social vulnerability. Conclusion: Despite a 9-fold increase in Lp(a) testing among US Veterans over the last decade, the overall testing rate remains extremely low. The steady proportion of Veterans with elevated Lp(a) over time supports the clinical utility of testing expansion. Efforts to increase testing, especially among Veterans living in neighborhoods with high social vulnerability, will be important to reduce emerging disparities as novel therapeutics to target Lp(a) become available.

Retinoid metabolism and its effects on the vasculature.

Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.

Clinical predictors of improvement in left ventricular ejection fraction in U.S. veterans with heart failure.

Background: Our understanding of the factors associated with improvement of LVEF and a heart failure with improved EF (HFimpEF) phenotype remains incomplete. Methods: We conducted a retrospective study using a national database of patients followed in the Veterans Affairs (VA) health system with serial assessment of left ventricular ejection fraction (LVEF) by echocardiography. We identified US veterans with a new diagnosis of heart failure with: (i) LVEF of <40 % in the 12 months prior to diagnosis, and (ii) follow-up LVEF assessment at least 6 months after their diagnosis. We defined HFimpEF as a final LVEF of ≥40 %. Results: Among the 106,414 US veterans with an initial LVEF of <40 % in this analysis, 39,994 (37.6 %) had a final EF of >40 % after a median follow up of 5 years. Multivariate regression analysis identified several factors that were independently associated with LVEF improvement including female sex, younger age, higher BMI, and a history of specific comorbid conditions such as hypertension, valve disease, atrial fibrillation, connective tissue disease, liver disease, and malignancy (p < 0.001). Conversely, a history of ischemic heart disease and peripheral arterial disease, as well as specific racial backgrounds (Black and Hispanic) were associated with lower rates of LVEF improvement. The model c-statistic for predicting LVEF improvement was 0.70. Conclusions: This large, detailed dataset facilitated an analysis of a large number of variables that significantly associated with HFimpEF; however, their combined discriminatory value for LVEF improvement remained modest, underscoring the complexity of the gene-environment-treatment interactions that govern LV function.

Effective Access to Care in a Crisis Period: Hypertension Control During the COVID-19 Pandemic by Telemedicine.

OBJECTIVE: To assess the effectiveness of telemedicine video visits in the management of hypertensive patients at home during the first year of the COVID-19 pandemic. METHODS: A quantitative analysis was performed of all home video visits coded with a diagnosis of essential hypertension during the first 12 months of the COVID-19 pandemic (March 2020 through February 2021). A total of 10,634 patients with 16,194 hypertension visits were present in our national telemedicine practice database during this time. Among this population, a total of 569 patients who had 1785 hypertension visits met the criteria of having 2 or more blood pressure (BP) readings, with the last BP reading occurring in the report period. We analyzed baseline characteristics and BP trends of these 569 patients during the study period. Voluntarily submitted patient satisfaction ratings, which were systematically requested at the end of each visit, were also analyzed. RESULTS: The mean age of the patients in this study cohort of 569 patients was 43.9 years, and 48.3% (275) were women. More than 62% (355) of the patients had an initial systolic BP (SBP) above 140 mm Hg, and 25.3% (144) had an initial SBP of greater than 160 mm Hg. The average number of visits during the study period was 3.1 visits per patient; an average of 6.4 BP measurements per patient were available. During the study period, 77% (438) of the patients experienced an improvement in either SBP or diastolic BP (DBP), with mean reductions of -9.7 mm Hg and -6.8 mm Hg in SBP and DBP, respectively. A total of 416 patients in the cohort started with a BP above 140/90 mm Hg. For this subset of patients, 55.7% (232) achieved a BP of 140/90 mm Hg or lower by the end of the study period, and the average reductions in SBP and DBP were -17.9 mm Hg and -12.8 mm Hg, respectively, which corresponded to improvements of 11.2% and 12.4%. These improvements did not vary significantly when patients were stratified by age, sex, or geographic region of residence (rural vs urban/suburban). Voluntarily submitted patient surveys indicated a high degree of patient satisfaction, with a mean satisfaction score of 4.94 (5-point scale). CONCLUSION: Clinician-patient relationships established in a video-first telemedicine model were broadly effective for addressing suboptimally controlled hypertension. Patient satisfaction with these visits was high.

Nontargeted mass spectrometry of dried blood spots for interrogation of the human circulating metabolome.

Advances in high-resolution, nontargeted mass spectrometry allow for the simultaneous measure of thousands of metabolites in a single biosample. Application of these analytical approaches to population-scale human studies has been limited by the need for resource-intensive blood sample collection, preparation, and storage. Dried blood spotting, a technique developed decades ago for newborn screening, may offer a simple approach to overcome barriers in human blood acquisition and storage. In this study, we find that over 4,400 spectral features across diverse chemical classes may be efficiently and reproducibly extracted and relatively quantified from human dried blood spots using nontargeted metabolomic analysis employing HILIC and reversed-phase liquid chromatography coupled to Orbitrap mass spectrometry. Moreover, over 80% of metabolites were found to be chemically stable in dried blood spots stored at room temperature for up to a week. In direct relation to plasma samples, dried blood spots exhibited comparable representation of the human circulating metabolome, capturing both known and previously uncharacterized metabolites. Dried blood spot approaches provide an opportunity for rapid and facile human biosampling and storage and will enable widespread metabolomics study of populations, particularly in resource-limited areas.

Increased Risk of Progression of Coronary Artery Calcification in Male Subjects with High Baseline Waist-to-Height Ratio: The Kangbuk Samsung Health Study.

BACKGROUND: The waist-to-height ratio (WHtR) is an easy and inexpensive adiposity index that reflects central obesity. In this study, we examined the association of baseline WHtR and progression of coronary artery calcification (CAC) over 4 years of follow-up in apparently healthy Korean men. METHODS: A total of 1,048 male participants (mean age, 40.9 years) in a health-screening program in Kangbuk Samsung Hospital, Seoul, Korea who repeated a medical check-up in 2010 and 2014 were recruited. Baseline WHtR was calculated using the value for the waist in 2010 divided by the value for height in 2010. The CAC score (CACS) of each subject was measured by multi-detector computed tomography in both 2010 and 2014. Progression of CAC was defined as a CACS change over 4 years greater than 0. RESULTS: During the follow-up period, progression of CAC occurred in 278 subjects (26.5%). The subjects with CAC progression had slightly higher but significant baseline WHtR compared to those who did not show CAC progression (0.51±0.04 vs. 0.50±0.04, P<0.01). The proportion of subjects with CAC progression significantly increased as the baseline WHtR increased from the 1st quartile to 4th quartile groups (18.3%, 18.7%, 28.8%, and 34.2%; P<0.01). The risk for CAC progression was elevated with an odds ratio of 1.602 in the 4th quartile group of baseline WHtR even after adjustment for confounding variables (95% confidence interval, 1.040 to 2.466). CONCLUSION: Increased baseline WHtR was associated with increased risk for CAC progression. WHtR might be a useful screening tool to identify individuals at high risk for subclinical atherosclerosis.

A resident-created hospitalist curriculum for internal medicine housestaff.

The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016;11:646-649. © 2016 Society of Hospital Medicine.

The cell cycle regulator p27Kip1 interacts with MCM7, a DNA replication licensing factor, to inhibit initiation of DNA replication.

The G1/S phase restriction point is a critical checkpoint that interfaces between the cell cycle regulatory machinery and DNA replicator proteins. Here, we report a novel function for the cyclin-dependent kinase inhibitor p27Kip1 in inhibiting DNA replication through its interaction with MCM7, a DNA replication protein that is essential for initiation of DNA replication and maintenance of genomic integrity. We find that p27Kip1 binds the conserved minichromosome maintenance (MCM) domain of MCM7. The proteins interact endogenously in vivo in a growth factor-dependent manner, such that the carboxyl terminal domain of p27Kip1 inhibits DNA replication independent of its function as a cyclin-dependent kinase inhibitor. This novel function of p27Kip1 may prevent inappropriate initiation of DNA replication prior to S phase.

Transcriptional profiling of in vitro smooth muscle cell differentiation identifies specific patterns of gene and pathway activation.

Mesodermal and epidermal precursor cells undergo phenotypic changes during differentiation to the smooth muscle cell (SMC) lineage that are relevant to pathophysiological processes in the adult. Molecular mechanisms that underlie lineage determination and terminal differentiation of this cell type have received much attention, but the genetic program that regulates these processes has not been fully defined. Study of SMC differentiation has been facilitated by development of the P19-derived A404 embryonal cell line, which differentiates toward this lineage in the presence of retinoic acid and allows selection for cells adopting a SMC fate through a differentiation-specific drug marker. We sought to define global alterations in gene expression by studying A404 cells during SMC differentiation with oligonucleotide microarray transcriptional profiling. Using an in situ 60-mer array platform with more than 20,000 mouse genes derived from the National Institute on Aging clone set, we identified 2,739 genes that were significantly upregulated after differentiation was completed (false-detection ratio <1). These genes encode numerous markers known to characterize differentiated SMC, as well as many unknown factors. We further characterized the sequential patterns of gene expression during the differentiation time course, particularly for known transcription factor families, providing new insights into the regulation of the differentiation process. Changes in genes associated with specific biological ontology-based pathways were evaluated, and temporal trends were identified for functional pathways. In addition to confirming the utility of the A404 model, our data provide a large-scale perspective of gene regulation during SMC differentiation.

Retinaldehyde dehydrogenase 1 deficiency inhibits PPARγ-mediated bone loss and marrow adiposity.

PPARγ, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARγ-activating anti-diabetic thiazolidinediones in clinical use promote marrow adiposity, bone loss, and skeletal fractures. As such, delineating novel regulatory pathways that modulate the action of PPARγ, and its obligate heterodimeric partner RXR, may have important implications for our understanding and treatment of disorders of low bone mineral density. We present data here establishing retinaldehyde dehydrogenase 1 (Aldh1a1) and its substrate retinaldehyde (Rald) as novel determinants of PPARγ-RXR actions in the skeleton. When compared to wild type (WT) controls, retinaldehyde dehydrogenase-deficient (Aldh1a1(-/-)) mice were protected against bone loss and marrow adiposity induced by either the thiazolidinedione rosiglitazone or a high fat diet, both of which potently activate the PPARγ-RXR complex. Consistent with these results, Rald, which accumulates in vivo in Aldh1a1(-/-) mice, protects against rosiglitazone-mediated inhibition of osteoblastogenesis in vitro. In addition, Rald potently inhibits in vitro adipogenesis and osteoclastogenesis in WT mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) respectively. Primary Aldh1a1(-/-) HSCs also demonstrate impaired osteoclastogenesis in vitro compared to WT controls. Collectively, these findings identify Rald and retinoid metabolism through Aldh1a1 as important novel modulators of PPARγ-RXR transactivation in the marrow niche.

Hypoxia: a master regulator of microRNA biogenesis and activity.

Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short noncoding RNAs that regulate gene expression through posttranscriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in the expression of a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated in order to integrate into the complex hierarchical regulatory network induced by hypoxia.

Deficiency of retinaldehyde dehydrogenase 1 induces BMP2 and increases bone mass in vivo.

The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-) ) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1(-/-) mice. In serum assays, Aldh1a1(-/-) mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1(-/-) mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1(-/-) mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1(-/-) mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling.

Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue.

Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.

Retinaldehyde dehydrogenase 1 coordinates hepatic gluconeogenesis and lipid metabolism.

Recent data link vitamin A and its retinoid metabolites to the regulation of adipogenesis, insulin sensitivity, and glucose homeostasis. Retinoid metabolism is tightly controlled by an enzymatic network in which retinaldehyde dehydrogenases (Aldh1-3) are the rate-limiting enzymes that convert retinaldehyde to retinoic acid. Aldh1a1-deficient mice are protected from diet-induced obesity and hence diabetes. Here we investigated whether Aldh1a1 and the retinoid axis regulate hepatic glucose and lipid metabolism independent of adiposity. The impact of Aldh1a1 and the retinoid pathway on glucose homeostasis and lipid metabolism was analyzed in hepatocytes in vitro and in chow-fed, weight-matched Aldh1a1-deficient vs. wild-type (WT) mice in vivo. Aldh1a1-deficient mice displayed significantly decreased fasting glucose concentrations compared with WT controls as a result of attenuated hepatic glucose production. Expression of key gluconeogenic enzymes as well as the activity of Forkhead box O1 was decreased in Aldh1a1-deficient vs. WT livers. In vitro, retinoid or cAMP agonist stimulation markedly induced gluconeogenesis in WT but not Aldh1a1-deficient primary hepatocytes. Aldh1a1 deficiency increased AMP-activated protein kinase α activity, decreased expression of lipogenic targets of AMP-activated protein kinase α and significantly attenuated hepatic triacylglycerol synthesis. In metabolic cage studies, lean Aldh1a1-deficient mice manifested enhanced oxygen consumption and reduced respiratory quotient vs. WT controls, consistent with increased expression of fatty acid oxidation markers in skeletal muscle. Taken together, this work establishes a role for retinoid metabolism in glucose homeostasis in vivo and for Aldh1a1 as a novel determinant of gluconeogenesis and lipid metabolism independent of adiposity.