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SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

Admixed populations constitute a large portion of global human genetic diversity, yet they are often left out of genomics analyses. This exclusion is problematic, as it leads to disparities in the understanding of the genetic structure and history of diverse cohorts and the performance of genomic medicine across populations. Admixed populations have particular statistical challenges, as they inherit genomic segments from multiple source populations—the primary reason they have historically been excluded from genetic studies. In recent years, however, an increasing number of statistical methods and software tools have been developed to account for and leverage admixture in the context of genomics analyses. Here, we provide a survey of such computational strategies for the informed consideration of admixture to allow for the well-calibrated inclusion of mixed ancestry populations in large-scale genomics studies, and we detail persisting gaps in existing tools. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Few studies have described the broader experience of survivors of female genital mutilation or cutting (FGM/C) who have sought asylum in the United States. To gain a better understanding of their exposure to gender-based violence (GBV), the study was conducted to help uncover themes and patterns of co-occurring individual and community factors among women asylum seekers who experienced FGM/C before they arrived in the United States. Following a retrospective chart review of FGM/C cases seen in a human rights clinic, 35 women met the inclusion criteria. The constant comparative method (CCM) was used to develop themes derived from clients' personal declarations and physicians' affidavits. A qualitative analysis revealed extensive histories of violence-physical, psychological, and sexual-demonstrating that FGM/C is only part of a larger arc of violence. Key themes developed via CCM include the experience of FGM/C, cultural attitudes toward FGM/C, cultural attitudes toward women, the lack of agency felt by women, silence around experiences of GBV and the constant reinforcement of that silence, the role of education in women's lives, and acts of resistance and social support. Placing FGM/C within its cultural context allows for a better understanding of its role in society's broader subjugation of women and elucidates how these social structures are maintained. For health care and other service providers, the high frequency of multiple forms of violence and the ingrained nature of women's oppression indicate the need for trauma-informed care and services as well as accessible resources beyond those explicitly related to FGM/C.

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult-to-treat RAS-mutant cancer.Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo.Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (Celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyperactivation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, such as metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacologic inhibitors of RAF (LY3009120), MEK (trametinib), or AMPK (compound C). The combination was found to be specific for RAS/RAF–mutant cells and had no significant effect in RAS/RAF–wild-type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared with each single-agent treatment.Conclusions: Combination sorafenib and aspirin exerts cytotoxicity against RAS/RAF–mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers. Clin Cancer Res; 24(5); 1090–102. ©2017 AACR.

Supplementary Figure 1, Sorafenib in combination with aspirin but not COX1/2 inhibitors synergistically induces cell death in RAS or RAF mutant cancer cell lines. Supplementary Figure 2, the combination of sorafenib/aspirin activates ERK and AMPK signalling after 4 hours of drug exposure. Supplementary Figure 3, MEK, pan-RAF and AMPK inhibitors diminish sorafenib/aspirin induced cell death. Supplementary Figure 4, high concentrations of dabrafenib in combination with aspirin reduces cell viability in RAS mutant cancer cells. Supplementary Figure 5, immunohistochemistry of phosphor-ERK in A549 xenografts treated with vehicle, sorafenib, aspirin or combined sorafenib/aspirin. Supplementary Table 1, list of used antibodies.

Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA-approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4

Background The phytohormone ethylene controls many processes in plant development and acts as a key signaling molecule in response to biotic and abiotic stresses: it is rapidly induced by flooding, wounding, drought, and pathogen attack as well as during abscission and fruit ripening. In kiwifruit (Actinidia spp.), fruit ripening is characterized by two distinct phases: an early phase of system-1 ethylene biosynthesis characterized by absence of autocatalytic ethylene, followed by a late burst of autocatalytic (system-2) ethylene accompanied by aroma production and further ripening. Progress has been made in understanding the transcriptional regulation of kiwifruit fruit ripening but the regulation of system-1 ethylene biosynthesis remains largely unknown. The aim of this work is to better understand the transcriptional regulation of both systems of ethylene biosynthesis in contrasting kiwifruit organs: fruit and leaves. Results A detailed molecular study in kiwifruit (A. chinensis) revealed that ethylene biosynthesis was regulated differently between leaf and fruit after mechanical wounding. In fruit, wound ethylene biosynthesis was accompanied by transcriptional increases in 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS), ACC oxidase (ACO) and members of the NAC class of transcription factors (TFs). However, in kiwifruit leaves, wound-specific transcriptional increases were largely absent, despite a more rapid induction of ethylene production compared to fruit, suggesting that post-transcriptional control mechanisms in kiwifruit leaves are more important. One ACS member, AcACS1, appears to fulfil a dominant double role; controlling both fruit wound (system-1) and autocatalytic ripening (system-2) ethylene biosynthesis. In kiwifruit, transcriptional regulation of both system-1 and -2 ethylene in fruit appears to be controlled by temporal up-regulation of four NAC (NAM, ATAF1/2, CUC2) TFs (AcNAC1–4) that induce AcACS1 expression by directly binding to the AcACS1 promoter as shown using gel-shift (EMSA) and by activation of the AcACS1 promoter in planta as shown by gene activation assays combined with promoter deletion analysis. Conclusions Our results indicate that in kiwifruit the NAC TFs AcNAC2–4 regulate both system-1 and -2 ethylene biosynthesis in fruit during wounding and ripening through control of AcACS1 expression levels but not in leaves where post-transcriptional/translational regulatory mechanisms may prevail.

Questions surrounding the timing, extent, and evolutionary consequences of archaic admixture into human populations have a long history in evolutionary anthropology. More recently, advances in human genetics, particularly in the field of ancient DNA, have shed new light on the question of whether or not Homo sapiens interbred with other hominin groups. By the late 1990s, published genetic work had largely concluded that archaic groups made no lasting genetic contribution to modern humans; less than a decade later, this conclusion was reversed following the successful DNA sequencing of an ancient Neanderthal. This reversal of consensus is noteworthy, but the reasoning behind it is not widely understood across all academic communities. There remains a communication gap between population geneticists and paleoanthropologists. In this review, we endeavor to bridge this gap by outlining how technological advancements, new statistical methods, and notable controversies ultimately led to the current consensus.

Previous studies have shown the conversion of the perennial kiwifruit (Actinidia spp.) to continuously flowering allows rapid cycling of generations. These plants are smaller, flower earlier and do...

BACKGROUND: Genome-wide association studies (GWAS) have demonstrated that psychopathology phenotypes are affected by many risk alleles with small effect (polygenicity). It is unclear how ubiquitously evolutionary pressures influence the genetic architecture of these traits. METHODS: We partitioned SNP heritability to assess the contribution of background (BGS) and positive selection, Neanderthal local ancestry, functional significance, and genotype networks in 75 brain-related traits (8,411≤N≤1,131,181, mean N=205,289). We applied binary annotations by dichotomizing each measure based on top 2%, 1%, and 0.5% of all scores genome-wide. Effect size distribution features were calculated using GENESIS. We tested the relationship between effect size distribution descriptive statistics and natural selection. In a subset of traits, we explore the inclusion of diagnostic heterogeneity (e.g., number of diagnostic combinations and total symptoms) in the tested relationship. RESULTS: SNP-heritability was enriched (false discovery rate q

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute’s Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African–European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants. Tractor is a statistical framework that facilitates the inclusion of admixed individuals in association studies by leveraging local ancestry. Tractor generates accurate ancestry-specific effect-size estimates and improves the resolution of association signals.

Volatile esters are key compounds contributing to flavor intensity in commonly consumed fruits including apple (Malus domestica), strawberry (Fragaria spp.), and banana (Musa sapientum). In kiwifruit (Actinidia spp.), ethyl butanoate and other esters have been proposed to contribute fruity, sweet notes to commercial cultivars. Here, we investigated the genetic basis for ester production in Actinidia in an A. chinensis mapping population (AcMPO). A major quantitative trait loci for the production of multiple esters was identified at the high-flavor intensity (HiFI) locus on chromosome 20. This locus co-located with eight tandemly arrayed alcohol acyl transferase genes in the Red5 genome that were expressed in a ripening-specific fashion that corresponded with ester production. Biochemical characterization suggested two genes at the HiFI locus, alcohol acyl transferase 16-b/c (AT16-MPb/c), probably contributed most to the production of ethyl butanoate. A third gene, AT16-MPa, probably contributed more to hexyl butanoate and butyl hexanoate production, two esters that segregated in AcMPO. Sensory analysis of AcMPO indicated that fruit from segregating lines with high ester concentrations were more commonly described as being “fruity” as opposed to “beany”. The downregulation of AT16-MPa–c by RNAi reduced ester production in ripe “Hort16A” fruit by >90%. Gas chromatography-olfactometry indicated the loss of the major “fruity” notes contributed by ethyl butanoate. A comparison of unimproved Actinidia germplasm with those of commercial cultivars indicated that the selection of fruit with high concentrations of alkyl esters (but not green note aldehydes) was probably an important selection trait in kiwifruit cultivation. Understanding ester production at the HiFI locus is a critical step toward maintaining and improving flavor intensity in kiwifruit.

Large-scale next-generation sequencing datasets have been transformative for informing clinical variant interpretation and as reference panels for statistical and population genetic efforts. While such resources are often treated as ground truth, we find that in widely used reference datasets such as the Genome Aggregation Database (gnomAD), some variants pass gold standard filters yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies due to technological artifacts rather than a true relationship to the phenotype. Here, we describe this phenomenon of discordant genotype calls across genotype discovery approaches, characterize the error mode of wrong calls, provide a blacklist of discordant sites identified in gnomAD that should be treated with caution in analyses, and present a metric and machine learning classifier trained on gnomAD data to identify likely discordant variants in other datasets. We find that different genotype discovery approaches have different sets of variants at which this problem occurs but that there are characteristic variant features that can be used to predict discordant behavior. Discordant sites are largely shared across ancestry groups, though different populations are powered for discovery of different variants. We find that the most common error mode is that of a variant being heterozygous for one approach and homozygous for the other, with heterozygous in the genomes and homozygous reference in the exomes making up the majority of miscalls.

Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47–0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS. Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70–1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38–1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80–1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18–0.65) among β-blocker users and 0.59 (95% CI 0.48–0.71) among those not using β-blockers. Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Description, A unique four-plexed RT-LAMP test kit operated by health workers can provide faster, more sensitive results than laboratory tests., RNA amplification tests sensitively detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but their complexity and cost are prohibitive for expanding coronavirus disease 2019 (COVID-19) testing. We developed “Harmony COVID-19,” a point-of-care test using inexpensive consumables, ready-to-use reagents, and a simple device. Our ready-to-use, multiplexed reverse transcription, loop-mediated isothermal amplification (RT-LAMP) can detect down to 0.38 SARS-CoV-2 RNA copies/μl and can report in 17 min for high–viral load samples (5000 copies/μl). Harmony detected 97 or 83% of contrived samples with ≥0.5 viral particles/μl in nasal matrix or saliva, respectively. Evaluation in clinical nasal specimens (n = 101) showed 100% detection of RNA extracted from specimens with ≥0.5 SARS-CoV-2 RNA copies/μl, with 100% specificity in specimens positive for other respiratory pathogens. Extraction-free analysis (n = 29) had 95% success in specimens with ≥1 RNA copies/μl. Usability testing performed first time by health care workers showed 95% accuracy.

Involuntary sterilization is a violation of human rights and grounds for asylum in the United States. Forensic medical evaluations can be useful in documenting this form of persecution and supporting asylees' claims for immigration relief. We conducted a retrospective case analysis of the personal and medical affidavits of 14 asylum-seeking women from four Latin America countries who all reported they had been involuntarily sterilized. Sixty-four percent said that "consent" was coerced; the remainder were unaware of having been sterilized at the time of the procedure. In all cases, findings on hysterosalpingogram were consistent with sterilization, revealing that all 14 had undergone a tubal ligation. Eighty-six percent of the women had been sterilized at the time of childbirth. The healthcare providers involved in the 14 cases failed to obtain informed consent, misled patients about sterilization, engaged in discriminatory behavior, and/or breached patient confidentiality regarding their HIV-status. All 14 asylum cases were defensive; of the 7 cases (50%) that have been decided to date, 100% have been granted asylum.

PROBLEM Most Americans indicate they are religious and/or spiritual and wish to have their beliefs taken into account when engaging with health care providers, yet gaps in medical education and health care practice remain. To underscore the importance of spirituality as a significant social determinant of health, a team at the Icahn School of Medicine at Mount Sinai in New York developed mandatory spirituality and health training for students integrated into all 4 years of the undergraduate medical education curriculum. APPROACH From 2014 to 2020, a small group of faculty took an innovative approach, launching the initiative and expanding the team by engaging interprofessional faculty and staff from across the institution. The team used an iterative process to integrate 4 distinct modules into 4 existing courses, spanning the four years of medical school. OUTCOMES The majority of students found that the spirituality and health curriculum was valuable to training and professional development. They appreciated the importance of patients' spiritual needs; valued learning about the role chaplains play in patient care and how initiate a consult; and indicated they intended to integrate spiritual history-taking in their patient care. With respect to process, 3 key factors-establishing an interprofessional team, working through an iterative process, and integrating the curriculum into existing courses-were critical to designing and implementing the modules. NEXT STEPS The team aims to expand and improve the curriculum by linking learning to specific standardized competencies as well as developing more specific performance assessments to demonstrate achievement of competencies. Professional development efforts will be enhanced so faculty can better model and reinforce the integration of spirituality into health care practices, and expand the curriculum on spirituality and health into graduate medical education.

Aroma is a critical factor influencing consumer acceptability of ripe fruit. When fruit are eaten, the aroma travels retronasally from the mouth into the olfactory receptors located in the nose after exhaling. In kiwifruit (Actinidia spp.), terpene volatiles such as α-terpinolene and 1,8-cineole have been shown to contribute to the characteristic aroma of ripe fruit. Notably, 1,8-cineole contributes a key floral/eucalyptus note to the aroma of ripe A. chinensis ‘Hort16A’ kiwifruit, based on sensory descriptive and discriminant analysis. Emission of α-terpinolene and 1,8-cineole in kiwifruit is induced by ethylene, and production peaks when fruit are at eating ripeness. Two monoterpene synthase TPS-b family genes have been isolated from the fruit of A. arguta and A. chinensis that produce α-terpinolene and 1,8-cineole, respectively. Here we discuss terpene volatiles with respect to fruit aroma and consumer sensory evaluation, analyze the gene structure and conserved motifs of TPS-b genes in published kiwifruit genomes and then construct a transcriptional regulatory network based on Actinidia TPS-b. These data provide further insights into the potential molecular mechanisms underlying signature monoterpene synthesis to improve flavor in kiwifruit.

Many academics ask ‘How can I use my research to influence policy?’. In this paper, we draw on our first-hand experience as social researchers for the British Government to advise how academics can create and communicate research with policymakers. Specifically, we describe methods of communicating research to policymakers in relation to research we undertook to listen to farmers about their priorities for a new agricultural policy for England following the exit of the UK from the European Union. The main purpose of this research was to ensure farmers’ voices were included in policy development and therefore communication of the research to policymakers was key. We reflect on the effectiveness of the communication methods we employed and summarise our learnings into four practical recommendations: (1) make research relevant to policymakers; (2) invest time to develop and maintain relationships with policymakers; (3) utilise ‘windows of opportunity’; and (4) adapt presentation and communication styles to the audience. We consider that employing these recommendations will help to improve how evidence is communicated between academia and government and therefore the influence of evidence in decision-making processes.

Dual loyalty is defined as, particularly as it pertains to the field of medicine, a conflict or potential conflict between a healthcare professional's simultaneous obligations–expressed or ...

Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.

We present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

A bidirectional and complex relationship exists between bone and glycemia. Persons with type 2 diabetes (T2D) are at risk for bone loss and fracture, however, heightened osteoanabolism may ameliorate T2D-induced deficits in glycemia as bone-forming osteoblasts contribute to energy metabolism via increased glucose uptake and cellular glycolysis. Mice globally lacking Nuclear Matrix Protein 4 (Nmp4), a transcription factor expressed in all tissues and conserved between humans and rodents, are healthy and exhibit enhanced bone formation in response to anabolic osteoporosis therapies. To test whether loss of Nmp4 similarly impacted bone deficits caused by diet induced obesity, male wild type (WT) and Nmp4(−/−) mice (8wks) were fed either low-fat diet (LFD) or high-fat diet (HFD) for 12wks. Endpoint parameters included bone architecture, structural and estimated tissue level mechanical properties, body weight/composition, glucose-stimulated insulin secretion, glucose tolerance, insulin tolerance and metabolic cage analysis. HFD diminished bone architecture and ultimate force and stiffness equally in both genotypes. Unexpectedly, the Nmp4(−/−) mice exhibited deficits in pancreatic β-cell function and were modestly glucose intolerant under normal diet conditions. Despite the β-cell deficits, the Nmp4(−/−) mice were less sensitive to HFD-induced weight gain, increases in % fat mass, and decreases in glucose tolerance and insulin sensitivity. We conclude that Nmp4 supports pancreatic β-cell function but suppresses peripheral glucose utilization, perhaps contributing to its suppression of induced skeletal anabolism. Selective disruption of Nmp4 in peripheral tissues may provide a strategy for improving both induced osteoanabolism and energy metabolism in comorbid patients.