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1.
Revisiting preeclampsia: a metabolic disorder of the placenta.
Hu, M, Li, J, Baker, PN, Tong, C
The FEBS journal. 2022;(2):336-354
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Abstract
Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide, impacting the long-term health of both mother and offspring. PE has long been characterized by deficient trophoblast invasion into the uterus and consequent placental hypoperfusion, yet the upstream causative factors and effective interventional targets for PE remain unknown. Alterations in the metabolism of preeclamptic placentas are thought to result from placental ischemia, while disturbances of the metabolism and of metabolites in PE pathogenesis are largely ignored. In fact, as one of the largest fetal organs at birth, the placenta consumes a considerable amount of glucose and fatty acid. Increasing evidence suggests glucose and fatty acid exist as energy substrates and regulate placental development through bioactive derivates. Moreover, recent findings have revealed that the placental metabolism adapts readily to environmental changes, altering its response to nutrients and endocrine signals; this adaptability optimizes pregnancy outcomes by diversifying available carbon sources for energy production, hormone synthesis, angiogenesis, immune activation, and tolerance, and fetoplacental growth. These observations raise the possibility that carbohydrate and lipid metabolism abnormalities play a role in both the etiology and clinical progression of PE, sparking a renewed interest in the interrelationship between PE and metabolic dysregulation. This review will focus on key metabolic substrates and regulatory molecules in the placenta and aim to provide novel insights with respect to the metabolism's role in modulating placental development and functions. Further investigations from this perspective are poised to decipher the etiology of PE and suggest potential therapies.
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Analysis of sex-based differences in energy substrate utilization during moderate-intensity aerobic exercise.
Cano, A, Ventura, L, Martinez, G, Cugusi, L, Caria, M, Deriu, F, Manca, A
European journal of applied physiology. 2022;(1):29-70
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Abstract
PURPOSE To explore sex-based differences in energy substrate utilization during moderate-intensity aerobic exercise; to identify the underpinning candidate physiological mechanisms. METHODS Three databases were searched from inception to August 2020. Pertinent studies quantifying the utilization of substrates during moderate aerobic exercise in healthy men and reproductive-age women were considered. Studies conducted on sedentary/recreationally active and athletic populations were included and analyzed separately. RESULTS Thirty-five studies entered the meta-analysis (21 in sedentary/recreationally active, 14 in athletic populations). Compared to women, the respiratory exchange ratio was significantly higher both in sedentary (mean difference, MD: + 0.03; p < 0.00001) and athletic men (MD: + 0.02; p < 0.0001). Greater carbohydrate oxidation was observed both in sedentary (standardized MD, SMD: 0.53; p = 0.006) and athletic men (SMD: 1.24; p < 0.00001). Regarding lipid substrates, sedentary men oxidized less fat than women (SMD: - 0.77; p = 0.0002), while no sex-based differences in fat oxidation were observed in athletes (SMD: 0.06; p = 0.77). Paucity of data prevented robust meta-analyses for protein sources. Sex hormones and different adrenergic activation were the most cited mechanisms to discuss sex-based differences. CONCLUSIONS Meta-analyses confirmed that men display greater reliance on carbohydrates while women rely more on lipids to sustain moderate aerobic exercise. The latter finding was not confirmed in athletes, a novel aspect of the present study. Mechanistically driven research is needed to further dissect the physiological underpinnings of sex differences in substrate utilization during aerobic exercise, especially for proteins, which are still less investigated than other substrates.
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Mechanism of Action of Acupuncture in Obesity: A Perspective From the Hypothalamus.
Wang, L, Yu, CC, Li, J, Tian, Q, Du, YJ
Frontiers in endocrinology. 2021;:632324
Abstract
Obesity is a prevalent metabolic disease caused by an imbalance in food intake and energy expenditure. Although acupuncture is widely used in the treatment of obesity in a clinical setting, its mechanism has not been adequately elucidated. As the key pivot of appetite signals, the hypothalamus receives afferent and efferent signals from the brainstem and peripheral tissue, leading to the formation of a complex appetite regulation circuit, thereby effectively regulating food intake and energy homeostasis. This review mainly discusses the relationship between the hypothalamic nuclei, related neuropeptides, brainstem, peripheral signals, and obesity, as well as mechanisms of acupuncture on obesity from the perspective of the hypothalamus, exploring the current evidence and therapeutic targets for mechanism of action of acupuncture in obesity.
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Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease.
Henriques, BJ, Katrine Jentoft Olsen, R, Gomes, CM, Bross, P
Gene. 2021;:145407
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Abstract
Electron transfer flavoprotein (ETF) is an enzyme with orthologs from bacteria to humans. Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. ETF functions as a hub taking up electrons from at least 14 flavoenzymes, feeding them into the respiratory chain. This represents a major source of reducing power for the electron transport chain from fatty acid oxidation and amino acid degradation. Transfer of electrons from the donor enzymes to ETF occurs by direct transfer between the enzyme bound flavins, a process that is tightly regulated by the polypeptide chain and by protein:protein interactions. ETF, in turn relays electrons to the iron sulfur cluster of the inner membrane protein ETF:QO, from where they travel via the FAD in ETF:QO to ubiquinone, entering the respiratory chain at the level of complex III. ETF recognizes its dehydrogenase partners via a recognition loop that anchors the protein on its partner followed by dynamic movements of the ETF flavin domain that bring redox cofactors in close proximity, thus promoting electron transfer. Genetic mutations in the ETFA or ETFB genes cause the Mendelian disorder multiple acyl-CoA dehydrogenase deficiency (MADD; OMIM #231680). We here review the knowledge on human ETF and investigations of the effects of disease-associated missense mutations in this protein that have promoted the understanding of the essential role that ETF plays in cellular metabolism and human disease.
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Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation.
Kitada, K, Kidoguchi, S, Nakano, D, Nishiyama, A
Journal of pharmacological sciences. 2021;(3):245-250
Abstract
Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.
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Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity-Breast Cancer Links.
Bustamante-Marin, XM, Merlino, JL, Devericks, E, Carson, MS, Hursting, SD, Stewart, DA
Frontiers in endocrinology. 2021;:632284
Abstract
The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
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Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution.
Parsons, RB, Facey, PD
Biomolecules. 2021;(10)
Abstract
Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.
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Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.
Fila, M, Chojnacki, C, Chojnacki, J, Blasiak, J
Nutrients. 2021;(12)
Abstract
The mechanisms of migraine pathogenesis are not completely clear, but 31P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.
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Ovarian, breast, and metabolic changes induced by androgen treatment in transgender men.
Pirtea, P, Ayoubi, JM, Desmedt, S, T'Sjoen, G
Fertility and sterility. 2021;(4):936-942
Abstract
Gender-affirming hormone therapy (GAHT) is often provided to transgender people. In this review of the literature, the current knowledge of ovarian, breast, and metabolic changes (body composition, insulin resistance, bone density, cardiovascular risk factors such as lipids, blood pressure, and hematocrit) observed following GAHT in adult transgender men is discussed. A body of literature concurs to describe that long-term androgen therapy in transgender men exerts atrophic effects on the breast. There is currently no evidence of an increased risk of breast cancer. Long-term testosterone treatment induces ovarian effects that become visible after 6 months of therapy. These changes consist of both macroscopic and microscopic alterations of ovarian morphology that mimic the typical ovarian aspect encountered in women with polycystic ovary syndrome but without an effect on antral follicle count. Metabolic effects of long-term androgen treatment in transgender men put them at par with cisgender men in terms of lipid profile, insulin resistance, and overall mortality. Body composition changes as desired after testosterone administration in most transgender men, and insulin resistance decreases with virilization. There are no detrimental effects on bone mineral density. Cardiometabolic risk and morbidity data are currently reassuring, even if certain studies show conflicting results. An increase in blood pressure and a decrease in high-density lipoprotein cholesterol have been reported as risk factors, whereas polycythemia is rare and treatable. Most available data are observational and based on biochemical markers instead of the more direct measures of cardiovascular damage. An explanation for these observed changes is mostly lacking. Psychological stress and lifestyle factors are often forgotten in a much needed integrated approach.
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Where are all the men? Low energy availability in male cyclists: A review.
Schofield, KL, Thorpe, H, Sims, ST
European journal of sport science. 2021;(11):1567-1578
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Abstract
Most of the low energy availability (LEA) research has been conducted in female populations. The occurrence of LEA in male athletes is not well known, even with an understanding of the components involved in and contributing to LEA. Cycling is a major risk factor for LEA due to inherent sports characteristics: low impact, high energy demands, and a common perception that leanness is a performance advantage. The purpose of this review is to discuss the cycling-specific studies that have documented components of RED-S. The review demonstrates male cyclists (1) experience energy deficits daily, weekly and throughout a season; (2) exhibit lower bone mineral density at the spine compared to the hip, and low bone mineral density correlating with LEA and; (3) demonstrate downregulation of the endocrine system with elevated cortisol, reduced testosterone and insulin-like growth factor 1. The complexity of LEA is further explored by the socio-psychological contribution that may impact eating behaviours, and therefore increase the risk of developing LEA. Future research directions include applying multifaceted research methods to gain a greater understanding of this syndrome and the effect of LEA on male cyclists.