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.     

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.     

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.     

Calorie restriction and the nutrient sensing signaling pathways

Calorie restriction (CR) is the most potent regimen known to extend the life span in multiple species. CR has also been shown to ameliorate several age-associated disorders in mammals and perhaps humans. CR induces diverse metabolic changes in organisms, and it is currently unclear whether and how these metabolic changes lead to life span extension. Recent studies in model systems have provided insight into the molecular mechanisms by which CR extends life span. In this review, we summarize and provide recent updates on multiple nutrient signaling pathways that have been connected to CR and longevity regulation. The roles of highly conserved longevity regulators – the Sirtuin family – in CR are also discussed. Received 25 August 2006; received after revision 9 October 2006; accepted 13 December 2006     

The obesity-related pathology and Th17 cells

Chronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORγt) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORγt.     

The neuroligin and neurexin families: from structure to function at the synapse

Proper brain connectivity and neuronal transmission rely on the accurate assembly of neurotransmitter receptors, cell adhesion molecules and several other scaffolding and signaling proteins at synapses. Several new exciting findings point to an important role for the neuroligin family of adhesion molecules in synapse development and function. In this review, we summarize current knowledge of the structure of neuroligins and neurexins, their potential binding partners at the synapse. We also discuss their potential involvement in several aspects of synapse development, including induction, specificity and stabilization. The implication of neuroligins in cognitive disorders such as autism and mental retardation is also discussed. Received 6 February 2006; received after revision 17 March 2006; accepted 26 April 2006     

Metabolic circuits in neural stem cells

Metabolic activity indicative of cellular demand is emerging as a key player in cell fate decision. Numerous studies have demonstrated that diverse metabolic pathways have a critical role in the control of the proliferation, differentiation and quiescence of stem cells. The identification of neural stem/progenitor cells (NSPCs) and the characterization of their development and fate decision process have provided insight into the regenerative potential of the adult brain. As a result, the potential of NSPCs in cell replacement therapies for neurological diseases is rapidly growing. The aim of this review is to discuss the recent findings on the crosstalk among key regulators of NSPC development and the metabolic regulation crucial for the function and cell fate decisions of NSPCs. Fundamental understanding of the metabolic circuits in NSPCs may help to provide novel approaches for reactivating neurogenesis to treat degenerative brain conditions and cognitive decline.     

Genetic studies of diseases

Functional imaging techniques such as positron and single-photon emission tomography exploit the relationship between neural activity, energy demand and cerebral blood flow to functionally map the brain. Despite the fact that neurobiological processes are not completely understood, several results have revealed the signals that trigger the metabolic and vascular changes accompanying variations in neural activity. Advances in this field have demonstrated that release of the major excitatory neurotransmitter glutamate initiates diverse signaling processes between neurons, astrocytes and blood perfusion, and that this signaling is crucial for the occurrence of brain imaging signals. Better understanding of the neural sites of energy consumption and the temporal correlation between energy demand, energy consumption and associated cerebrovascular hemodynamics gives novel insight into the potential of these imaging tools in the study of metabolic neurodegenerative disorders.     

Developmental and pathological angiogenesis in the central nervous system

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.     

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.     

Stress,glucocorticoid receptors,and adult neurogenesis: a balance between excitation and inhibition?

Adult neurogenesis, the birth of new neurons in the mature brain, has attracted considerable attention in the last decade. One of the earliest identified and most profound factors that affect adult neurogenesis both positively and negatively is stress. Here, we review the complex interplay between stress and adult neurogenesis. In particular, we review the role of the glucocorticoid receptor, the main mediator of the stress response in the proliferation, differentiation, migration, and functional integration of newborn neurons in the hippocampus. We review a multitude of mechanisms regulating glucocorticoid receptor activity in relationship to adult neurogenesis. We postulate a novel concept in which the level of glucocorticoid receptor expression directly regulates the excitation-inhibition balance, which is key for proper neurogenesis. We furthermore argue that an excitation-inhibition dis-balance may underlie aberrant functional integration of newborn neurons that is associated with psychiatric and paroxysmal brain disorders.     

Memory

Progress towards amelioration and eventual cure of human cognitive disorders requires understanding the molecular signaling mechanisms that normally govern learning and memory. The fly Drosophila melanogaster has been instrumental in the identification of molecules and signaling pathways essential for learning and memory, because genetic screens have produced mutants in these processes and the system facilitates integrated genetic, molecular, histological and behavioral analyses. We discuss the behavioral paradigms available to assess associative learning and memory in the fly, the contributions learning and memory mutants have made to our understanding of the molecular mechanisms that govern learning and memory, and predictions stemming from the nature of the affected genes. Furthermore, we consider the multiple well-established behavioral assays available and the powerful molecular genetics of the fly with regard to development of models of human cognitive disorders and their pharmacological treatment.     

Regulatory T cells, mTOR kinase, and metabolic activity

The field that links immunity and metabolism is rapidly expanding. Apparently, non-immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation, suggesting that metabolic alterations can be induced by or be a consequence of an altered self-immune tolerance. In this context, a key role is played by signaling systems acting as metabolic “sensors” linking energy/nutritional status to regulatory T (Treg) cell functions. We propose that a dynamic/oscillatory activity of intracellular metabolism, through mTOR modulation, might represent a shift in understanding the molecular mechanisms governing Treg cell tolerance. In particular, the decision between Treg cell proliferation and hyporesponsiveness arises from their ability to probe the extracellular milieu and, modulating the metabolic intracellular signaling, to determine different qualitative and quantitative functional outcomes.