Intake, absorption and synthesis of fatty acids, including those produced by the intestinal microbiota are tightly monitored via specific receptors and, indirectly through their conversion into a ...variety of signalling molecules. The resulting information is integrated and translated to different physiological processes, including the regulation of appetite and satiation. Direct chemosensing of fatty acids takes place via interaction with free fatty acid (FFA) and other receptors. These are present in the oronasal cavity and along the entire gastrointestinal tract, in various other tissues, and, for some receptors also in brain. Results from early studies have suggested differences between fatty acids in their ability to induce the release of satiety hormones or their short-term effects on food-intake. However, more recent findings indicate that this has limited impact on long-term energy intake. Similarly, pharmacological strategies for appetite control via modulation of peripheral fatty acid binding receptors have not met their expectations. Regarding the psychobiology of eating behaviour, there has been a shift towards emphasising the importance of food reward and the cephalic phase response. Lipid-rich foods are highly energy dense. During evolution this has stimulated the development of reward mechanisms, in which fatty acids, in conjunction with carbohydrates, are major triggers. Fatty acids are also precursors of endocannabinoids and their structural congeners. The endocannabinoid system (ECS) plays a pivotal role in the homeostatic and non-homeostatic regulation of eating behaviour. In the brain it links to different endocrine and neuronal pathways, including dopaminergic circuits in the mesocorticolimbic system such as the ventral tegmental area and the nucleus accumbens, which are crucial for hedonic eating. Despite the vast progress made in the field of neurobiology it is clear that eating behaviour, one of our strongest instincts, still possess major scientific challenges. The failure, already a decade ago, of the cannabinoid-receptor type 1 (CB1) blockers for treatment of overweight and its complications may serve as an illustration that ‘single-target’ approaches to modulate, or even understand-, over- or undereating are very unrealistic.
Demonstrating in an unambiguous manner that a diet, let alone a single product, ‘optimizes’ health, presents an enormous challenge. The least complicated is when the starting situation is clearly ...suboptimal, like with nutritional deficiencies, malnutrition, unfavourable lifestyle, or due to disease or ageing. Here, desired improvements and intervention strategies may to some extent be clear. However, even then situations require approaches that take into account interactions between nutrients and other factors, complex dose-effect relationships etc. More challenging is to substantiate that a diet or a specific product optimizes health in the general population, which comes down to achieve perceived, ‘non-medical’ or future health benefits in predominantly healthy persons. Presumed underlying mechanisms involve effects of non-nutritional components with subtle and slowly occurring physiological effects that may be difficult to translate into measurable outcomes. Most promising strategies combine classical physiological concepts with those of ‘multi-omics’ and systems biology. Resilience-the ability to maintain or regain homeostasis in response to stressors-is often used as proxy for a particular health domain. Next to this, quantifying health requires personalized strategies, measurements preferably carried out remotely, real-time and in a normal living environment, and experimental designs other than randomized controlled trials (RCTs), for example N-of-1 trials.
Traditional foods and diets can provide health benefits beyond their nutrient composition because of the presence of bioactive compounds. In various traditional healthcare systems, diet-based ...approaches have always played an important role, which has often survived until today. Therefore, investigating traditional foods aimed at health promotion could render not only novel bioactive substances but also mechanistic insights. However, compared to pharmacologically focused research on natural products, investigating such nutrition-based interventions is even more complicated owing to interacting compounds, less potent and relatively subtle effects, the food matrix, and variations in composition and intake. At the same time, technical advances in 'omics' technologies, cheminformatics, and big data analysis create new opportunities, further strengthened by increasing insights into the biology of health and homeostatic resilience. These are to be combined with state-of-the-art ethnobotanical research, which is key to obtaining reliable and reproducible data. Unfortunately, socioeconomic developments and climate change threaten traditional use and knowledge as well as biodiversity.
ABSTRACT
Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a ...shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT
2C
agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed.
Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status ...and dietary patterns directly influence activity of the ECS. Following a general introduction on the functioning of the ECS, the present review specifically addresses its role in the modulation of hedonic eating. Humans possess strong motivational systems triggered by rewarding aspects of food. Food reward is comprised of two components: one appetitive (orienting towards food); the other consummatory (hedonic evaluation), also referred to as ‘wanting’ and ‘liking’, respectively. Endocannabinoid tone seems to influence both the motivation to feed and the hedonic value of foods, probably by modifying palatability. Human physiology underlying hedonic eating is still not fully understood. A better understanding of the role of the ECS in the rewarding value of specific foods or diets could offer new possibilities to optimise the balance between energy and nutrient intake for different target groups. These groups include the obese and overweight, and potentially individuals suffering from malnutrition. Examples for the latter group are patients with disease-related anorexia, as well as the growing population of frail elderly suffering from persistent loss of food enjoyment and appetite resulting in malnutrition and involuntary weight loss. It has become clear that the psychobiology of food hedonics is extremely complex and the clinical failure of CB1 inverse agonists including rimonabant (Accomplia®) has shown that ‘quick wins’ in this field are unlikely.
Mitochondrial dynamics in cancer-induced cachexia van der Ende, Miranda; Grefte, Sander; Plas, Rogier ...
Biochimica et biophysica acta. Reviews on cancer,
12/2018, Letnik:
1870, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cancer-induced cachexia has a negative impact on quality of life and adversely affects therapeutic outcomes and survival rates. It is characterized by, often severe, loss of muscle, with or without ...loss of fat mass. Insight in the pathophysiology of this complex metabolic syndrome and direct treatment options are still limited, which creates a research demand. Results from recent studies point towards a significant involvement of muscle mitochondrial networks. However, data are scattered and a comprehensive overview is lacking. This paper aims to fill existing knowledge gaps by integrating published data sets on muscle protein or gene expression from cancer-induced cachexia animal models. To this end, a database was compiled from 94 research papers, comprising 11 different rodent models. This was combined with four genome-wide transcriptome datasets of cancer-induced cachexia rodent models. Analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved ROS detoxification and mitophagy is increased. Our results underline the relevance of including post-translational modifications of key proteins involved in mitochondrial functioning in future studies on cancer-induced cachexia.
► Seeds of wild fruits of Rubus and Sambucus species were analysed. ► Fatty acid profile and tocopherol content of the oils were determined. ► Antioxidant activity and total phenolic contents were ...evaluated. ► In vitro anti-inflammatory activities were assessed. ► Rubus seeds have strong antioxidant and anti-inflammatory properties.
Fruit seeds are byproducts from fruit processing. Characterisation of the bioactive compounds present in seeds and evaluation of their potential biological properties is therefore of particular importance in view of a possible valorisation of seeds as a source of health beneficial components. In this work, we have analysed the seeds of Sambucus and Rubus species in order to identify their bioactive components and to determine the antioxidant and anti-inflammatory activities of the extracts. We first analysed their oil content, in order to assess the fatty acid profile and tocopherol content. Moreover, the methanolic extracts of the seeds were analysed for their total phenolic contents and antioxidant capacities. Polyphenols were identified by HPLC–ESI–MS/MS analysis. Furthermore, extracts were evaluated for their inhibitory effects on the production of LPS-induced inflammatory mediators (NO, CCL-20) in RAW 264.7 cells.
Our findings show that the methanolic extracts from Rubus seeds have strong antioxidant and anti-inflammatory properties and could therefore represent an attractive source of bioactive compounds for food, cosmetic, or pharmaceutical applications.
Arabinoxylans of various structures and sources have shown to possess the ability to induce a range of immune responses in different cell types in vitro and in vivo. Although the underlying ...mechanisms remain to be fully established, several studies point towards the involvement of activation of pattern recognition receptors (PRRs). Activation of specific PRRs (i.e., Dectin-1 and CR3) has also been shown to play a key role in the induction of a non-specific memory response in innate immune cells, termed ‘trained innate immunity’. In the current study, we assessed whether arabinoxylans are also able to induce trained innate immunity. To this end, a range of arabinoxylan preparations from different sources were tested for their physicochemical properties and their capacity to induce innate immune training and resilience. In human macrophages, rice and wheat-derived arabinoxylan preparations induced training and/or resilience effects, the extent depending on fiber particle size and solubility. Using a Dectin-1 antagonist or a CR3 antibody, it was demonstrated that arabinoxylan-induced trained immunity in macrophages is mainly dependent on Dectin-1b. These findings build on previous observations showing the immunomodulatory potential of arabinoxylans as biological response modifiers and open up promising avenues for their use as health promoting ingredients.
•Wheat- and rice-derived arabinoxylan preparations induced innate immune training and resilience in human macrophages in vitro.•TNF-α release of macrophages correlated strongly with the degree of insolubility and particle size.•Arabinoxylan-induced trained immunity in human macrophages is mainly dependent on interaction with C-type lectin receptor Dectin-1b.
Docosahexaenoyl ethanolamide (DHEA), the ethanolamine conjugate of the n-3 long chain polyunsaturated fatty acid docosahexaenoic acid, is endogenously present in the human circulation and in tissues. ...Its immunomodulating properties have been (partly) attributed to an interaction with the cyclooxygenase-2 (COX-2) enzyme. Recently, we discovered that COX-2 converts DHEA into two oxygenated metabolites, 13- and 16-hydroxylated-DHEA (13- and 16-HDHEA, respectively). It remained unclear whether these oxygenated metabolites also display immunomodulating properties like their parent DHEA. In the current study we investigated the immunomodulating properties of 13- and 16-HDHEA in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compounds reduced production of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-1Ra, but did not affect nitric oxide (NO) and IL-6 release. Transcriptome analysis showed that the compounds inhibited the LPS-mediated induction of pro-inflammatory genes (InhbA, Ifit1) and suggested potential inhibition of regulators such as toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 3 (IRF3), whereas anti-inflammatory genes (SerpinB2) and potential regulators IL-10, sirtuin 1 (Sirt-1), fluticasone propionate were induced. Additionally, transcriptome analysis of 13-HDHEA suggests a potential anti-angiogenic role. In contrast to the known oxylipin-lowering effects of DHEA, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses revealed that 13- and 16-HDHEA did not affect oxylipin formation. Overall, the anti-inflammatory effects of 13-HDHEA and 16-HDHEA are less pronounced compared to their parent molecule DHEA. Therefore, we propose that COX-2 metabolism of DHEA acts as a regulatory mechanism to limit the anti-inflammatory properties of DHEA.
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•13- and 16-HDHEA are recently discovered COX-2 metabolites with unknown effects.•13- and 16-HDHEA reduce TNFα, IL-1β, IL-1Ra in LPS-stimulated RAW264.7 macrophages.•Expression/pathway analyses show an anti-inflammatory profile for 13- and 16-HDHEA.•DHEA but not 13- and 16-HDHEA reduce LPS-induced prostaglandin formation.•13- and 16-HDHEA may be products of DHEA inactivation through COX-2.
•Common dietary fatty acids, including palmitic, stearic, and oleic acid, have been associated with changes of behaviors, including ingestive behaviors, and cognitive functioning in humans and in ...animal models.•These fatty acids have numerous effects on synaptic function, protein trafficking, and gene transcription in cellular and in vitro experimental systems.•Although effects of dietary (exogenous) fatty acids on CNS inflammatory pathways, direct neuronal actions are less-explored and offer an opportunity for additional mechanisms affecting ingestive behaviors and energy homeostasis.•Polyunsaturated fatty acids likewise have cellular signaling capabilities and serve as precursors for endocannabinoids.•Fatty acids also serve as precursors for endocannabinoids and structurally related compounds that are involved in regulating homeostatic and non-homeostatic eating behavior via cannabinoid (CB1) and other receptors located on cell-membranes and intracellular compartments.•Notwithstanding its complexity and the failure of CB1 blockers as drugs for weight management, the endocannabinoid system still holds promises to modulate food intake, in particular in relation to increasing the intake of (specific) foods in target groups.
Common dietary fatty acids, including palmitic acid, stearic acid, oleic acid, and polyunsaturated fatty acids, have been studied in the context of overall dietary fat and shown to impact on several types of behaviors, most prominently cognitive behaviors and ingestive behaviors. The independent effects of these fatty acids have been less well-delineated. Several studies implicate these common fatty acids in modulation of the CNS immune/inflammatory response as a key mediator of behavioral effects. However, signaling actions of the fatty acids to regulate cell structure and neuronal or synaptic function have been identified in numerous studies, and the relevance or contribution(s) of these to ingestive behavioral outcomes represent an area for future study. Finally, fatty acids are precursors of endocannabinoids and their structural congeners. Being highly dynamic and complex, the endocannabinoid system plays a key role ingestive behavior via cellular and synaptic mechanisms, thus representing another important area for future study.
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