Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO), which are clinically ...associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in the mammalian embryonic brain and suggest NSC self renewal as a cellular mechanism underlying the association between IEMs and autism.
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•TMLHE controls the neural stem cell (NSC) pool in the embryonic mouse neocortex•CPT1A and fatty acid mobilization from lipid droplets regulate the NSC pool•TMLHE deficiencies lead to increased symmetric differentiating division of NSCs•NSC defects under TMLHE deficiencies can be rescued by exogenous carnitine
The mechanisms underlying the association between inborn errors of fatty acid metabolism and developmental brain disorders such as autism remain unclear. Xie et al. find that TMLHE, a carnitine biosynthesis enzyme, and carnitine-dependent long-chain fatty acid β-oxidation control the neural stem cell pool during neocortical development by maintaining self-renewing divisions.
Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention ...has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling. However, many tissues play important roles in synergistically regulating metabolic homeostasis and should be considered part of a network. Our approach identifies redox as an acute regulator of the greater metabolic network. Redox reactions involve the transfer of electrons between two molecules and in this work refer to commonly shared molecules, reflective of energy state, that can readily lose electrons to increase or gain electrons to decrease the oxidation state of molecules including NAD(P), NAD(P)H, and thiols. Metabolism alters such redox molecules to impact metabolic function in many tissues, thus, responding to anabolic and catabolic stimuli appropriately and synergistically. It is also important to consider environmental factors that have arisen or increased in recent decades as putative modifiers of redox and reactive oxygen species (ROS) and thus metabolic state. ROS are highly reactive, controlled by the thiol redox state and influence the function of thousands of proteins. Lactate (L) and pyruvate (P) in cells are present in a ratio of about 10 reflective of the cytosolic NADH to NAD ratio. Equilibrium is maintained in cells because lactate dehydrogenase is highly expressed and near equilibrium. The major source of circulating lactate and pyruvate is muscle, although other tissues also contribute. Acetoacetate (A) is produced primarily by liver mitochondria where β-hydroxybutyrate dehydrogenase is highly expressed, and maintains a ratio of β-hydroxybutyrate (β) to A of about 2, reflective of the mitochondrial NADH to NAD ratio. All four metabolites as well as the thiols, cysteine and glutathione, are transported into and out of cells, due to high expression of relevant transporters. Our model supports regulation of all collaborating metabolic organs through changes in circulating redox metabolites, regardless of whether change was initiated exogenously or by a single organ. Validation of these predictions suggests novel ways to understand function by monitoring and impacting redox state.
We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain ...acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins that mislead β-cells into perceiving nutrient excess when none exists. Thus, basal hyperinsulinemia is envisioned as an adaptation to sustained real or perceived nutrient excess that only manifests as a disease when the excess demand can no longer be met by an overworked β-cell. In this article we will present a testable hypothetical mechanism to explain the role of lipids and ROS in basal hyperinsulinemia and how they differ from glucose-stimulated insulin secretion (GSIS). The model centers on redox regulation, via ROS, and
-acylation-mediated trafficking via LC-CoA. These pathways are well established in neural systems but not β-cells. During GSIS, these signals rise and fall in an oscillatory pattern, together with the other well-established signals derived from glucose metabolism; however, their precise roles have not been defined. We propose that failure to either increase or decrease ROS or LC-CoA appropriately will disturb β-cell function.
Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain ...unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.
Accumulation of depolarized mitochondria within β‐cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual ...mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run’ pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψm) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non‐fusing mitochondria that were found to have reduced Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that before autophagy mitochondria lose Δψm and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.
One of the unique features of beta-cells is their relatively low expression of many antioxidant enzymes. This could render beta-cells susceptible to oxidative damage but may also provide a system ...that is sensitive to reactive oxygen species as signals. In isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H2O2. In both models, insulin secretion could be stimulated by provision of either exogenous H2O2 or diethyl maleate, which raises intracellular H2O2 levels. Provision of exogenous H2O2 scavengers, including cell permeable catalase and N-acetyl-L-cysteine, inhibited glucose-stimulated H2O2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H2O2, had no effect on GSIS. Because oxidative stress is an important risk factor for beta-cell dysfunction in diabetes, the relationship between glucose-induced H2O2 generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or INS-1(832/13) cells to oxidative stressors, including arsenite, 4-hydroxynonenal, and methylglyoxal, led to decreased GSIS. This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together, these findings suggest that H2O2 derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb its signaling function.
Fragility fractures present enormous health challenges for women. Dairy products provide many bone-beneficial nutrients, such as calcium and vitamin D. Individual dairy foods may exert different ...effects on bone health.
The aim of this study was to investigate the associations between total dairy, yogurt, milk, and cheese and fragility fracture risk among females in the prospective Nurses' Health Study (NHS) conducted in the United States.
In the current analysis, 103,003 females with mean age of 48 y were followed from 1980-2004. Proportional hazards models were used to estimate risk of first fracture (of the wrist, hip, or vertebrae) by intakes of dairy foods (total dairy, milk, yogurt, or cheese) obtained from a food frequency questionnaire. Fractures that were caused by high-trauma events were not included. We relied on self-reported data for wrist and hip fractures whereas for vertebral fractures, medical records were used to confirm cases.
A total of 5495 incident fracture cases were documented during follow-up. After controlling for relevant confounding variables, consumption of ≥2 servings/d of total dairy (compared with <1 serving/d) was associated with lower fracture risk (hazard ratio HR: 0.74; 95% confidence interval CI: 0.61, 0.89). More than 2 servings of milk per day (compared with <1 serving/d) were associated with a lower fracture risk (HR: 0.85; 95% CI: 0.77, 0.94). Intakes of calcium, vitamin D, and protein from nondairy sources did not modify the effects of total dairy or milk on fracture risk. There was no association between yogurt intake and fracture risk. Intake of cheese (≥1 servings/d compared with <1 serving/wk) was weakly associated with lower fracture risk (HR: 0.89; 95% CI: 0.79, 0.99).
Higher total dairy, milk, and cheese intakes are associated with lower risks of fracture in females in the NHS.
Food-induced anaphylaxis (FIA) is potentially life threatening. Prompt administration of epinephrine is universally recommended by current treatment guidelines.
To identify factors associated with ...early epinephrine treatment for FIA and to specifically examine the association between early epinephrine treatment and hospitalization.
A chart review study conducted at Hasbro Children's Hospital/Rhode Island Hospital. By using the International Classification of Diseases, Ninth Revision codes, we identified all patients who presented to the emergency department with FIA between January 1, 2004, and December 31, 2009. Early epinephrine treatment was defined as receipt of epinephrine before arrival to the emergency department. The independent association between early epinephrine treatment and hospitalization was assessed using logistic regression.
Among the 384 emergency department visits for FIA identified during the study period, 234 patients received epinephrine (61%). Among this subset, most (164 70%) received early epinephrine treatment, whereas a smaller number of patients (70 30%) first received epinephrine in the emergency department (late treatment). Patients who received early epinephrine treatment were older (7.4 vs 4.3 years; P = .008), were more likely to have a known food allergy (66% vs 34%; P < .001), and were more likely to own an epinephrine autoinjector (80% vs 23%; P < .001). Patients treated early were less likely to be hospitalized (17% vs 43%; P < .001). After adjusting for age, sex, and race, the patients who received early epinephrine treatment remained at significantly decreased risk of hospitalization compared with those who received late epinephrine treatment (odds ratio 0.25 95% CI, 0.12-0.49).
In this population, early treatment of FIA with epinephrine was associated with significantly lower risk of hospitalization. Accordingly, this study supports the benefit of prompt administration of epinephrine for the treatment of FIA.
Weight gain during the menopausal transition is common. Dairy consumption may impact weight change during this critical period, and different dairy foods may have different effects.
This study aimed ...to investigate the associations of different types of dairy foods with weight gain and risk of obesity in perimenopausal women from the Nurses’ Health Study II cohort.
The examination at menopause was selected as the exam closest to the reported age at menopause. Weight change during 12 y surrounding menopause was derived from self-reported weight data for 3 exams before and 3 after menopause. The mean age of the first weight measure was 45.8 y and the average BMI was 25.0 kg/m2. Dairy food intakes were estimated as mean intakes over the same 12 y. Generalized linear models were used to assess the association between dairy foods and annualized weight change. Cox proportional hazard models were used to estimate the adjusted relative risks for becoming obese over 12 y surrounding menopause.
In longitudinal analyses, those with the highest yogurt intakes had the lowest weight gain at every exam. This was not the case for other forms of dairy. After adjusting for potential covariates, those consuming ≥2.0 servings/wk of yogurt (compared with <1.0 serving/month) had a 31% (RR: 0.69; 95% CI: 0.64, 0.74) lower risk of obesity. The highest total dairy intake (≥2.0 servings/d compared with <1.0) was associated with only a 12% (RR: 0.88; 95% CI: 0.82, 0.95) reduction in obesity risk. Higher activity levels and alternative healthy eating index scores were independently associated with statistically significant reductions in risk of obesity, but higher intakes of yogurt strengthened these beneficial associations.
Yogurt intake was associated with less weight gain and lower obesity risk in women during the menopausal transition.
Energy access remains a challenge for many countries in sub-Saharan Africa. Ghana is no exception as 15% of her population live in remote areas without access to electricity. In 2015, the World Bank ...Group provided funding for the Ghanaian government to extend electricity to some of her rural island communities. The government of Ghana chose to deploy solar mini-grids. Despite technological breakthrough with solar mini-grids and financial support from the World Bank Group, the deployment of the solar mini-grids still faced significant barriers some of which are embedded in the socio-cultural contexts of the Ghanaian rural island communities. Designed through a socio-technical systems lens, this study explores the sociotechnical barriers and strategies to overcoming the barriers to deploying solar mini-grids in Ghanaian rural island communities. Data were collected through semistructured interviews, focus group discussions, and direct observations. The results show that different categories of barriers affected deployment of the solar mini-grids. The barriers are socio-technical in nature suggesting that the obstacles to renewable energy deployment in sub-Saharan Africa are neither exclusively social nor technical but a combination of both social and technical forces. While the social factors range from land disputes to illegal connections, the technical barriers include limited technical know-how to lack of qualified technicians. In suggesting strategies to address these barriers, the study participants proposed involvement of indigenes, training and transfer of technical expertise, and increased generation capacity. Based on these findings, the study outlines three policy implications on mitigating the barriers in future projects.
•Solar mini-grids deployment faced barriers in rural SSA.•Barriers to deploying solar mini-grids in the rural SSA are socio-technical factors.•Social and technical factors are both important to deploying solar mini-grids in rural SSA.•Social factors occupy an important place relating to energy transitions in rural SSA.
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