Hormonal control of Sertoli cell metabolism regulates spermatogenesis

Hormonal regulation is essential to spermatogenesis. Sertoli cells (SCs) have functions that reach far beyond the physical support of germ cells, as they are responsible for creating the adequate ionic and metabolic environment for germ cell development. Thus, much attention has been given to the metabolic functioning of SCs. During spermatogenesis, germ cells are provided with suitable metabolic substrates, in a set of events mediated by SCs. Multiple signaling cascades regulate SC function and several of these signaling pathways are hormone-dependent and cell-specific. Within the seminiferous tubules, only SCs possess receptors for some hormones rendering them major targets for the hormonal signaling that regulates spermatogenesis. Although the mechanisms by which SCs fulfill their own and germ cells metabolic needs are mostly studied in vitro, SC metabolism is unquestionably a regulation point for germ cell development and the hormonal control of these processes is required for a normal spermatogenesis.     

GPR120: a critical role in adipogenesis,inflammation, and energy metabolism in adipose tissue

It is well known that adipose tissue has a critical role in the development of obesity and metabolic diseases and that adipose tissue acts as an endocrine organ to regulate lipid and glucose metabolism. Accumulating in the adipose tissue, fatty acids serve as a primary source of essential nutrients and act on intracellular and cell surface receptors to regulate biological events. G protein-coupled receptor 120 (GPR120) represents a promising target for the treatment of obesity-related metabolic disorders for its involvement in the regulation of adipogenesis, inflammation, glucose uptake, and insulin resistance. In this review, we summarize recent studies and advances regarding the systemic role of GPR120 in adipose tissue, including both white and brown adipocytes. We offer a new perspective by comparing the different roles in a variety of homeostatic processes from adipogenic development to adipocyte metabolism, and we also discuss the effects of natural and synthetic agonists that may be potential agents for the treatment of metabolic diseases.     

Microbiome,probiotics and neurodegenerative diseases: deciphering the gut brain axis

The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastrointestinal tract communicates with the central nervous system through the gut–brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecular communication network that link systemic imbalances with the development of neurodegeneration including insulin regulation, fat metabolism, oxidative markers and immune signaling. Age is a common factor in the development of neurodegenerative disease and probiotics prevent many harmful effects of aging such as decreased neurotransmitter levels, chronic inflammation, oxidative stress and apoptosis—all factors that are proven aggravators of neurodegenerative disease. Indeed patients with Parkinson’s and Alzheimer’s diseases have a high rate of gastrointestinal comorbidities and it has be proposed by some the management of the gut microbiota may prevent or alleviate the symptoms of these chronic diseases.     

OX40 promotes obesity-induced adipose inflammation and insulin resistance

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4⁺ T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation. The effects of OX40 on IR are mechanistically linked to the promotion of T cell activation, Th1 cell differentiation and proliferation—as well as the attenuation of Treg suppressive activity and the enhancement of proinflammatory cytokine production—in adipose tissues. Furthermore, OX40 expression on T cells was positively associated with obesity in humans, suggesting that our findings are clinically relevant. In summary, our study revealed that OX40 in CD4⁺ T cells is crucial for adipose tissue inflammation and IR development. Therefore, the OX40 signaling pathway may be a new target for preventing or treating obesity-related IR and T2DM.     

Metabolic syndrome as a risk factor for neurological disorders

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.     

Including the mitochondrial metabolism of <Emphasis Type="SmallCaps">l</Emphasis>-lactate in cancer metabolic reprogramming

Glucose avidity, high glycolysis and l-lactate production, regardless of oxygen availability, are the main traits of cancer metabolic reprogramming. The idea that mitochondria are dysfunctional in cancer, thus causing a glycolysis increase for ATP production and l-lactate accumulation as a dead-end product of glucose catabolism, has oriented cancer research for many years. However, it was shown that mitochondrial metabolism is essential for cancer cell proliferation and tumorigenesis and that l-lactate is a fundamental energy substrate with tumor growth-promoting and signaling capabilities. Nevertheless, the known ability of mitochondria to take up and oxidize l-lactate has remained ignored by cancer research. Beginning with a brief overview of the metabolic changes occurring in cancer, we review the present knowledge of l-lactate formation, transport, and intracellular oxidation and underline the possible role of l-lactate metabolism as energetic, signaling and anabolic support for cancer cell proliferation. These unexplored aspects of cancer biochemistry might be exploited for therapeutic benefit.     

MicroRNA regulation and analytical methods in cancer cell metabolism

The reprogramming of glucose metabolism from oxidative to glycolytic metabolism, known as the Warburg effect, is an anomalous characteristic of cancer cell metabolism. Recent studies have revealed a subset of microRNAs (miRNAs) that play critical roles in regulating the reprogramming of glucose metabolism in cancer cells. These miRNAs regulate cellular glucose metabolism by directly targeting multiple metabolic genes, including those encoding key glycolytic enzymes. In the first part of this review, we summarized the recent knowledge of miRNA regulation in the reprogramming of glucose metabolism in cancer cells and discussed the potential utilization of the key miRNA regulators as metabolic targets for developing new antitumor agents. Then, we summarized recent advances in methods and techniques for studying miRNA regulation in cancer cell metabolism.     

Identification of Treg-like cells in <Emphasis Type="Italic">Tetraodon</Emphasis>: insight into the origin of regulatory T subsets during early vertebrate evolution

CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg cells) are critical for the maintenance of peripheral tolerance, and the suppression of autoimmune diseases and even tumors. Although Treg cells are well characterized in humans, little is known regarding their existence or occurrence in ancient vertebrates. In the present study, we report on the molecular and functional characterization of a Treg-like subset with the phenotype CD4-2⁺CD25-like⁺Foxp3-like⁺ from a pufferfish (Tetraodon nigroviridis) model. Functional studies showed that depletion of this subset produced an enhanced mixed lymphocyte reaction (MLR) and nonspecific cytotoxic cell (NCC) activity in vitro, as well as inflammation of the intestine in vivo. The data presented here will not only enrich the knowledge of fish immunology but will also be beneficial for a better cross-species understanding of the evolutionary history of the Treg family and Treg-mediated regulatory networks in cellular immunity.     

Macropinocytosis,mTORC1 and cellular growth control

The growth and proliferation of metazoan cells are driven by cellular nutrient status and by extracellular growth factors. Growth factor receptors on cell surfaces initiate biochemical signals that increase anabolic metabolism and macropinocytosis, an actin-dependent endocytic process in which relatively large volumes of extracellular solutes and nutrients are internalized and delivered efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth factor receptor signaling and the overall metabolic status of the cell are coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1 (mTORC1), which positively regulates protein synthesis and negatively regulates molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly binds to and activates mTORC1. Rag is activated by both lysosomal luminal and cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt, and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb converge at the lysosomal membrane, and several lines of evidence support the idea that growth factor-dependent endocytosis facilitates amino acid transfer into the lysosome leading to the activation of Rag. This review summarizes evidence that growth factor-stimulated macropinocytosis is essential for amino acid-dependent activation of mTORC1, and that increased solute accumulation by macropinocytosis in transformed cells supports unchecked cell growth.     

Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview

Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, α-ketoglutarate, and ATP serve as cofactors for chromatin-modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome–metabolome to speculate as to how this may influence autoimmune diseases.     

Regulation and dysregulation of astrocyte activation and implications in tumor formation

Astrocytic activation is a cellular response to disturbances of the central nervous system (CNS). Recent advances in cellular and molecular biology have demonstrated the remarkable changes in molecular signaling, morphology, and metabolism that occur during astrocyte activation. Based on these studies, it has become clear that the astrocyte activation process is regulated by a variety of signaling pathways, which result in metabolic support, wound healing and scar formation. While normal astrocyte activation pathways drive homeostasis and/or repair in the CNS, dysregulation of these pathways can lead to astrocyte abnormalities, including glioma formation with similar phenotypes as reactive astrocytes. We review the principle pathways responsible for astrocytic activation, as well as their potential contribution to tumor formation in the CNS.     

Sulfatase activities towards the regulation of cell metabolism and signaling in mammals

In higher vertebrates, sulfatases belong to a conserved family of enzymes that are involved in the regulation of cell metabolism and in developmental cell signaling. They cleave the sulfate from sulfate esters contained in hormones, proteins, and complex macromolecules. A highly conserved cysteine in their active site is post-translationally converted into formylglycine by the formylglycine-generating enzyme encoded by SUMF1 (sulfatase modifying factor 1). This post-translational modification activates all sulfatases. Sulfatases are extensively glycosylated proteins and some of them follow trafficking pathways through cells, being secreted and taken up by distant cells. Many proteoglycans, glycoproteins, and glycolipids contain sulfated carbohydrates, which are sulfatase substrates. Indeed, sulfatases operate as decoding factors for a large amount of biological information contained in the structures of the sulfated sugar chains that are covalently linked to proteins and lipids. Modifications to these sulfate groups have pivotal roles in modulating specific signaling pathways and cell metabolism in mammals.     

Adenine nucleotide metabolism during anoxia and postanoxic recovery in insects

Severe hypoxia (anoxia), if maintained for more than a few minutes, causes irreversible damage in humans and other mammals. Why mammals are so vulnerable to anoxia is not fully understood. It is therefore of interest to study animals that are more tolerant of anoxia in order to identify physiological and metabolic properties that are correlated with a high tolerance of anoxia. Insects have high metabolic rates and their energy metabolism is dependent on aerobic ATP production. In insects, as in mammals, anoxia causes a rapid breakdown of physiological function, resulting in a state similar to rigor mortis. This is accompanied by a precipitous decrease in metabolic rate. In contrast to mammals, however, insects can survive anoxia for many hours and recover spontaneously and completely when air is again available. We have followed the metabolism of adenine nucleotides in locust tissues (mainly in the flight muscle) over 3 h of anoxia and during recovery from 1 h of anoxia. The content of ATP in the flight muscle dropped to 1% of normal during 2 h of anoxia. The main product was AMP which increased in content more than 20-fold. Some of the AMP was deaminated to IMP and this was further dephosphorylated to inosine. Altogether less than 30% of the total adenine nucleotides were degraded during 3 h of anoxia and this may contribute to the amazing ability of insects to recover from prolonged anoxia.     

Interferons and indoleamine 2,3-dioxygenase: Role in antimicrobial and antitumor effects

Summary Indoleamine 2,3-dioxygenase (IDO) is an interferon (IFN)-induced protein that initiates the metabolism of tryptophan along the kynurenine pathway. Although IDO can be induced by IFN- in many cell types, only mononuclear phagocytes have been shown to be induced to decyclize tryptophan by all three IFN classes. Since tryptophan is an essential amino acid necessary for a variety of metabolic processes, depletion of available tryptophan may be an important mechanism for control of rapidly-dividing microbial pathogens and tumors. The purpose of this review is to present evidence that documents the effects of IFN-induced IDO on prokaryotic and eukaryotic pathogens, as well as on a variety of tumor cell lines.     

Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes

Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring.