Mitochondria: the gatekeepers between metabolism and immunity.

Metabolism and immunity are crucial monitors of the whole-body homeodynamics. All cells require energy to perform their basic functions. One of the most important metabolic skills of the cell is the ability to optimally adapt metabolism according to demand or availability, known as metabolic flexibility. The immune cells, first line of host defense that circulate in the body and migrate between tissues, need to function also in environments in which nutrients are not always available. The resilience of immune cells consists precisely in their high adaptive capacity, a challenge that arises especially in the framework of sustained immune responses. Pubmed and Scopus databases were consulted to construct the extensive background explored in this review, from the Kennedy and Lehninger studies on mitochondrial biochemistry of the 1950s to the most recent findings on immunometabolism. In detail, we first focus on how metabolic reconfiguration influences the action steps of the immune system and modulates immune cell fate and function. Then, we highlighted the evidence for considering mitochondria, besides conventional cellular energy suppliers, as the powerhouses of immunometabolism. Finally, we explored the main immunometabolic hubs in the organism emphasizing in them the reciprocal impact between metabolic and immune components in both physiological and pathological conditions.

Mitochondrial metabolism and neuroinflammation in the cerebral cortex and cortical synapses of rats: effect of milk intake through DNA methylation.

Brain plasticity and cognitive functions are tightly influenced by foods or nutrients, which determine a metabolic modulation having a long-term effect on health, involving also epigenetic mechanisms. Breast milk or formula based on cow milk is the first food for human beings, who, throughout their lives, are then exposed to different types of milk. We previously demonstrated that rats fed with milk derived from distinct species, with different compositions and nutritional properties, display selective modulation of systemic metabolic and inflammatory profiles through changes of mitochondrial functions and redox state in liver, skeletal and cardiac muscle. Here, in a rat model, we demonstrated that isoenergetic supplementation of milk from cow (CM), donkey (DM) or human (HM) impacts mitochondrial functions and redox state in the brain cortex and cortical synapses, affecting neuroinflammation and synaptic plasticity. Interestingly, we found that the administration of different milk modulates DNA methylation in rat brain cortex and consequently affects gene expression. Our results emphasize the importance of nutrition in brain and synapse physiology, and highlight the key role played in this context by mitochondria, nutrient-sensitive organelles able to orchestrate metabolic and inflammatory responses.

Hepatocyte Aquaporins AQP8 and AQP9 Are Engaged in the Hepatic Lipid and Glucose Metabolism Modulating the Inflammatory and Redox State in Milk-Supplemented Rats.

Milk is an important source of nutrients and energy, but there are still many uncertainties regarding the health effects of milk and dairy products consumption. Milk from different species varies in physicochemical and nutritional properties. We previously showed that dietary supplements with different milks in rats trigger significant differences in metabolic and inflammatory states, modulating mitochondrial functions in metabolically active organs such as the liver and skeletal muscle. Here, we have deepened the effects of isoenergetic supplementation of milk (82 kJ) from cow (CM), donkey (DM) or human (HM) on hepatic metabolism to understand the interlink between mitochondrial metabolic flexibility, lipid storage and redox state and to highlight the possible role of two hepatocyte aquaporins (AQPs) of metabolic relevance, AQP8 and AQP9, in this crosstalk. Compared with rats with no milk supplementation, DM- and HM-fed rats had reduced hepatic lipid content with enhanced mitochondrial function and decreased oxidative stress. A marked reduction in AQP8, a hydrogen peroxide channel, was seen in the liver mitochondria of DM-fed rats compared with HM-fed, CM-fed and control animals. DM-fed or HM-fed rats also showed reduced hepatic inflammatory markers and less collagen and Kupffer cells. CM-fed rats showed higher hepatic fat content and increased AQP9 and glycerol permeability. A role of liver AQP8 and AQP9 is suggested in the different metabolic profiles resulting from milk supplementation.

A Bioelectrical Impedance Analysis in Adult Subjects: The Relationship between Phase Angle and Body Cell Mass.

The correct assessment of body composition is essential for an accurate diagnostic evaluation of nutritional status. The body mass index (BMI) is the most widely adopted indicator for evaluating undernutrition, overweight, and obesity, but it is unsuitable for differentiating changes in body composition. In recent times, bioelectrical impedance analyses (BIA) have been proven as a more accurate procedure for the assessment of body composition. Furthermore, the efficiency of bioelectrical impedance vector analyses, as an indicator of nutritional status and hydration, has been demonstrated. By applying a bioimpedance analysis, it is possible to detect fat mass (FM), fat free mass (FFM), phase angle, and body cell mass (BCM). It is important to point out that phase angle and BCM are strongly associated with health status. The aim of this research was to examine body composition and the association between the phase angle and BCM in 87 subjects (14 males and 73 females), aged between 23 and 54 years, with BMIs ranging from 17.0 to 32.0 kg/m2, according to sex. The BMI results revealed that the majority of the assessed subjects were within the normal range and had a normal percentage of FM. Our data indicate that a direct relation exists between phase angle and cellular health and that these values increase almost linearly. Consequently, a high phase angle may be related to increased BCM values.

From Obesity-Induced Low-Grade Inflammation to Lipotoxicity and Mitochondrial Dysfunction: Altered Multi-Crosstalk between Adipose Tissue and Metabolically Active Organs.

Obesity is a major risk factor for several metabolic diseases, including type 2 diabetes, hyperlipidemia, cardiovascular diseases, and brain disorders. Growing evidence suggests the importance of inter-organ metabolic communication for the progression of obesity and the subsequent onset of related disorders. This review provides a broad overview of the pathophysiological processes that from adipose tissue dysfunction leading to altered multi-tissue crosstalk relevant to regulating energy homeostasis and the etiology of obesity. First, a comprehensive description of the role of adipose tissue was reported. Then, attention was turned toward the unhealthy expansion of adipose tissue, low-grade inflammatory state, metabolic inflexibility, and mitochondrial dysfunction as root causes of systemic metabolic alterations. In addition, a short spot was devoted to iron deficiency in obese conditions and the role of the hepcidin-ferroportin relationship in the management of this issue. Finally, different classes of bioactive food components were described with a perspective to enhance their potential preventive and therapeutic use against obesity-related diseases.

Impedance Analysis to Evaluate Nutritional Status in Physiological and Pathological Conditions.

A thorough knowledge of body composition assessment techniques is the cornerstone for initiating a customized nutritional program. The second step is to consider the potential of their application in different physiological and pathological conditions and their effectiveness in the management of a monitoring pathway during dietary interventions. To date, bioimpedance analysis is the most effective and reliable method for assessing body composition due to its advantages in terms of speed of execution, non-invasiveness and low cost. Therefore, this review article aims to analyze the main concepts and application areas of bioimpedance measurement techniques, in particular vector frequency-based analysis (BIVA) systems, in order to assess their validity in both physiological and pathological conditions.

Role of Milk Micronutrients in Human Health.

The aim of this review is to provide an overview of different compositions, in terms of main minerals and vitamins, of milk from animal species that represent the most common source of this food for humans, highlighting the uniqueness of nutritional qualities linked to animal species. It is known that milk is an important and valuable food for human nutrition, representing an excellent source of nutrients. Indeed, it contains both macronutrients (proteins, carbohydrates, and fat) that contribute to its nutritive and biological value and micronutrients represented by minerals and vitamins, which play a relevant role in the body's various vital functions. Although their supply is represented by small quantities, vitamins and minerals are important components for a healthy diet. Milk composition in terms of minerals and vitamins differs between various animal species. Micronutrients are important components for human health as their deficiency is causes of malnutrition. Furthermore, we report on the most significant metabolic and beneficial effects of certain micronutrients in the milk, emphasizing the importance of this food for human health and the need for some milk enrichment procedures with the most relevant micronutrients to human health.

Crosstalk between Adipose Tissue and Hepatic Mitochondria in the Development of the Inflammation and Liver Injury during Ageing in High-Fat Diet Fed Rats.

Obesity is considered an epidemic disorder, due to an imbalance between energy consumption and metabolizable energy intake. This balance is increasingly disrupted during normal aging processes due to the progressive impairment of mechanisms that normally control energy homeostasis. Obesity is triggered by an excessive lipid depots but reflects systemic inflammation along with large adipocytes secreting proinflammatory adipokines, an increase of the free fatty acids levels in the bloodstream, and ectopic lipid accumulation. Hepatic fat accumulation is the most common cause of chronic liver disease, characterized by mitochondrial dysfunction with a consequent impaired fat metabolism and increased oxidative stress. Therefore, mitochondrial dysfunction is associated to hepatic lipid accumulation and related complications. In this study, we assessed the crosstalk between adipose tissue and liver, analyzing the time-course of changes in hepatic mitochondrial fatty acid oxidation capacity versus fatty acid storage, focusing on the contribution of adipose tissue inflammation to hepatic lipid accumulation, using a rodent model of high fat diet-induced obesity. Our results demonstrate that both high-fat diet-induced obesity and aging induce dysregulation of adipose tissue function and similar metabolic alterations mediated by mitochondrial function impairment and altered inflammatory profile. The high fat diet-induced obesity anticipates and exacerbates liver mitochondrial dysfunction that occurs with aging processes.

The Hepatic Mitochondrial Alterations Exacerbate Meta-Inflammation in Autism Spectrum Disorders.

The role of the liver in autism spectrum disorders (ASD), developmental disabilities characterized by impairments in social interactions and repetitive behavioral patterns, has been poorly investigated. In ASD, it has been shown a dysregulation of gut-brain crosstalk, a communication system able to influence metabolic homeostasis, as well as brain development, mood and cognitive functions. The liver, with its key role in inflammatory and metabolic states, represents the crucial metabolic organ in this crosstalk. Indeed, through the portal vein, the liver receives not only nutrients but also numerous factors derived from the gut and visceral adipose tissue, which modulate metabolism and hepatic mitochondrial functions. Here, we investigated, in an animal model of ASD (BTBR mice), the involvement of hepatic mitochondria in the regulation of inflammatory state and liver damage. We observed increased inflammation and oxidative stress linked to hepatic mitochondrial dysfunction, steatotic hepatocytes, and marked mitochondrial fission in BTBR mice. Our preliminary study provides a better understanding of the pathophysiology of ASD and could open the way to identifying hepatic mitochondria as targets for innovative therapeutic strategies for the disease.

Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.

Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.

Heart Mitochondrial Metabolic Flexibility and Redox Status Are Improved by Donkey and Human Milk Intake.

The biological mechanisms linking nutrition and antioxidants content of the diet with cardiovascular protection are subject of intense investigation. It has been demonstrated that dietary supplementation with cow, donkey or human milk, characterized by distinct nutritional properties, triggers significant differences in the metabolic and inflammatory status through the modulation of hepatic and skeletal muscle mitochondrial functions. Cardiac mitochondria play a key role for energy-demanding heart functions, and their disfunctions is leading to pathologies. Indeed, an altered heart mitochondrial function and the consequent increased reactive oxygen species (ROS) production and inflammatory state, is linked to several cardiac diseases such as hypertension and heart failure. In this work it was investigated the impact of the milk consumption on heart mitochondrial functions, inflammation and oxidative stress. In addition, it was underlined the crosstalk between mitochondrial metabolic flexibility, lipid storage and redox status as control mechanisms for the maintenance of cardiovascular health.

Dietary Micronutrient Management to Treat Mitochondrial Dysfunction in Diet-Induced Obese Mice.

Obesity and associated metabolic disturbances, which have been increasing worldwide in recent years, are the consequences of unhealthy diets and physical inactivity and are the main factors underlying non-communicable diseases (NCD). These diseases are now responsible for about three out of five deaths worldwide, and it has been shown that they depend on mitochondrial dysfunction, systemic inflammation and oxidative stress. It was also demonstrated that several nutritional components modulating these processes are able to influence metabolic homeostasis and, consequently, to prevent or delay the onset of NCD. An interesting combination of nutraceutical substances, named DMG-gold, has been shown to promote metabolic and physical wellness. The aim of this research was to investigate the metabolic, inflammatory and oxidative pathways modulated by DMG-gold in an animal model with diet-induced obesity. Our data indicate that DMG-gold decreases the metabolic efficiency and inflammatory state and acts as an antioxidant and detoxifying agent, modulating mitochondrial functions. Therefore, DMG-gold is a promising candidate in the prevention/treatment of NCD.

Milk Fatty Acid Profiles in Different Animal Species: Focus on the Potential Effect of Selected PUFAs on Metabolism and Brain Functions.

Milk contains several important nutrients that are beneficial for human health. This review considers the nutritional qualities of essential fatty acids (FAs), especially omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) present in milk from ruminant and non-ruminant species. In particular, the impact of milk fatty acids on metabolism is discussed, including its effects on the central nervous system. In addition, we presented data indicating how animal feeding-the main way to modify milk fat composition-may have a potential impact on human health, and how rearing and feeding systems strongly affect milk quality within the same animal species. Finally, we have presented the results of in vivo studies aimed at supporting the beneficial effects of milk FA intake in animal models, and the factors limiting their transferability to humans were discussed.

Neurodevelopmental Disorders: Effect of High-Fat Diet on Synaptic Plasticity and Mitochondrial Functions.

Neurodevelopmental disorders (NDDs) include diverse neuropathologies characterized by abnormal brain development leading to impaired cognition, communication and social skills. A common feature of NDDs is defective synaptic plasticity, but the underlying molecular mechanisms are only partially known. Several studies have indicated that people's lifestyles such as diet pattern and physical exercise have significant influence on synaptic plasticity of the brain. Indeed, it has been reported that a high-fat diet (HFD, with 30-50% fat content), which leads to systemic low-grade inflammation, has also a detrimental effect on synaptic efficiency. Interestingly, metabolic alterations associated with obesity in pregnant woman may represent a risk factor for NDDs in the offspring. In this review, we have discussed the potential molecular mechanisms linking the HFD-induced metabolic dysfunctions to altered synaptic plasticity underlying NDDs, with a special emphasis on the roles played by synaptic protein synthesis and mitochondrial functions.

Interplay between Peripheral and Central Inflammation in Obesity-Promoted Disorders: The Impact on Synaptic Mitochondrial Functions.

The metabolic dysfunctions induced by high fat diet (HFD) consumption are not limited to organs involved in energy metabolism but cause also a chronic low-grade systemic inflammation that affects the whole body including the central nervous system. The brain has been considered for a long time to be protected from systemic inflammation by the blood-brain barrier, but more recent data indicated an association between obesity and neurodegeneration. Moreover, obesity-related consequences, such as insulin and leptin resistance, mitochondrial dysfunction and reactive oxygen species (ROS) production, may anticipate and accelerate the physiological aging processes characterized by systemic inflammation and higher susceptibility to neurological disorders. Here, we discussed the link between obesity-related metabolic dysfunctions and neuroinflammation, with particular attention to molecules regulating the interplay between energetic impairment and altered synaptic plasticity, for instance AMP-activated protein kinase (AMPK) and Brain-derived neurotrophic factor (BDNF). The effects of HFD-induced neuroinflammation on neuronal plasticity may be mediated by altered brain mitochondrial functions. Since mitochondria play a key role in synaptic areas, providing energy to support synaptic plasticity and controlling ROS production, the negative effects of HFD may be more pronounced in synapses. In conclusion, it will be emphasized how HFD-induced metabolic alterations, systemic inflammation, oxidative stress, neuroinflammation and impaired brain plasticity are tightly interconnected processes, implicated in the pathogenesis of neurological diseases.

Decreased Metabolic Flexibility in Skeletal Muscle of Rat Fed with a High-Fat Diet Is Recovered by Individual CLA Isomer Supplementation via Converging Protective Mechanisms.

Energy balance, mitochondrial dysfunction, obesity, and insulin resistance are disrupted by metabolic inflexibility while therapeutic interventions are associated with improved glucose/lipid metabolism in skeletal muscle. Conjugated linoleic acid mixture (CLA) exhibited anti-obesity and anti-diabetic effects; however, the modulatory ability of its isomers (cis9, trans11, C9; trans10, cis12, C10) on the metabolic flexibility in skeletal muscle remains to be demonstrated. Metabolic inflexibility was induced in rat by four weeks of feeding with a high-fat diet (HFD). At the end of this period, the beneficial effects of C9 or C10 on body lipid content, energy expenditure, pro-inflammatory cytokines, glucose metabolism, and mitochondrial efficiency were examined. Moreover, oxidative stress markers, fatty acids, palmitoyletanolamide (PEA), and oleyletanolamide (OEA) contents along with peroxisome proliferator-activated receptors-alpha (PPARα), AKT, and adenosine monophosphate-activated protein kinase (AMPK) expression were evaluated in skeletal muscle to investigate the underlying biochemical mechanisms. The presented results indicate that C9 intake reduced mitochondrial efficiency and oxidative stress and increased PEA and OEA levels more efficiently than C10 while the anti-inflammatory activity of C10, and its regulatory efficacy on glucose homeostasis are associated with modulation of the PPARα/AMPK/pAKT signaling pathway. Our results support the idea that the dissimilar efficacy of C9 and C10 against the HFD-induced metabolic inflexibility may be consequential to their ability to activate different molecular pathways.

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet-induced obese mice.

Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice. Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload.

High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction.

Brain mitochondrial dysfunction is involved in the development of neurological and neurodegenerative diseases. Mitochondria specifically located at synapses play a key role in providing energy to support synaptic functions and plasticity, thus their defects may lead to synaptic failure, which is a common hallmark of neurodegenerative diseases. High-Fat Diet (HFD) consumption increases brain oxidative stress and impairs brain mitochondrial functions, although the underlying mechanisms are not completely understood. The aim of our study is to analyze neuroinflammation and mitochondrial dysfunctions in brain cortex and synaptosomal fraction isolated from a mouse model of diet-induced obesity. Male C57Bl/6 mice were divided into two groups fed a standard diet or HFD for 18 weeks. At the end of the treatment, inflammation (detected by ELISA), antioxidant state (measured by enzymatic activity), mitochondrial functions and efficiency (detected by oxidative capacity and Seahorse analysis), and brain-derived neurotrophic factor (BDNF) pathway (analyzed by western blot) were determined in brain cortex and synaptosomal fraction. In HFD animals, we observed an increase in inflammatory parameters and oxidative stress and a decrease in mitochondrial oxidative capacity both in the brain cortex and synaptosomal fraction. These alterations parallel with modulation of BDNF, a brain key signaling molecule that is linking synaptic plasticity and energy metabolism. Neuroinflammation HFD-dependent negatively affects BDNF pathway and mitochondrial activity in the brain cortex. The effect is even more pronounced in the synaptic region, where the impaired energy supply may have a negative impact on neuronal plasticity.

Hemispheric Asymmetries in Radial Line Bisection: Role of Retinotopic and Spatiotopic Factors.

Previous studies showed that healthy individuals bisect radial lines oriented along the midsagittal plane farther than the true center (distal bisection bias). It was proposed that the distal bisection bias depended on the presence of an attention bias directed toward far space (distal attention bias) and that this bias is related to the activity of the occipitotemporal visual processing stream. Other studies have also suggested that a similar distal attention bias is linked to the activity of the right hemisphere. In the present experiment we investigated whether distal bisection bias increased when radial lines were placed in the left hemispace. Furthermore, we also examined whether the bisection bias was enhanced by the use of the left hand, as left hand movements are mainly controlled by the right hemisphere. Right-handed participants were asked to bisect radial lines presented below eye level along the midsagittal plane (central lines), or laterally and parallel to the midsagittal plane, in the left or right hemispace (left and right lines, respectively). Participants used their right or left hand. The results showed that participants consistently bisected left and central radial lines farther than (i) the true center and (ii) the subjective midpoint of right radial lines. Conversely, they bisected accurately right radial lines. The hand did not influence bisection error. The present study suggests that the distal bisection bias found in the bisection of left radial lines might depend on the presence of a distal attention bias related to right hemisphere activity. The relative contribution of retinotopic and spatiotopic factors in producing the distal bisection bias is discussed.

Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model.

Scope: The hypothalamus is a key brain region involved in the control of feeding and energy expenditure. Hypothalamic inflammation and oxidative stress are landmarks of both obesity and aging processes, although the molecular mechanisms are still unknown. Therefore, with the aim to understand the neurobiological mechanisms of energy homeostasis during aging, we evaluate the effects of long feeding high-fat diet (HFD) in rats, at different age, on modulation of hypothalamic molecular pathway, oxidative stress, and inflammation. Procedures: Male Wistar rats were divided into two groups: control group, receiving standard diet (CD), and treated group, receiving HFD. Both groups were treated with the appropriate diet for 1, 3, 6, 12, or 18 weeks. We investigated energy balance and body composition, as well as lipid profile, homeostatic model assessment index, and inflammatory state in serum. Furthermore, we also analyzed, at hypothalamic level, inflammation and oxidative stress, and adenosine monophosphate-dependent kinase (AMPK) and pAMPK expression levels. Results: Our data showed that aging and HFD induce increased energy intake and energy efficiency and decreased energy expenditure associated, at hypothalamic level, with inflammation and oxidative stress and activation of AMPK. Conclusion: Our results indicate that the age at which HFD feeding starts and the diet duration are critical in obesity development. The prolonged activation of hypothalamic AMPK may be related to the alterations in energy homeostasis.