A diet rich in fish oil and Leucine Ameliorates Hypercalcemia in tumour-induced cachectic mice

Background: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca2+ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). Methods: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca2+ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. Results: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca2+ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. Conclusion: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour

Lipidomics Reveals Multiple Pathway Effects of a Multi-Components Preparation on Lipid Biochemistry in ApoE*3Leiden.CETP Mice

Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. Methodology/Principal Findings: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p <0.001), CETP levels (-31%,

Cross-Species Comparison of Genes Related to Nutrient Sensing Mechanisms Expressed along the Intestine

Introduction Intestinal chemosensory receptors and transporters are able to detect food-derived molecules and are involved in the modulation of gut hormone release. Gut hormones play an important role in the regulation of food intake and the control of gastrointestinal functioning. This mechanism is often referred to as “nutrient sensing”. Knowledge of the distribution of chemosensors along the intestinal tract is important to gain insight in nutrient detection and sensing, both pivotal processes for the regulation of food intake. However, most knowledge is derived from rodents, whereas studies in man and pig are limited, and cross-species comparisons are lacking. Aim To characterize and compare intestinal expression patterns of genes related to nutrient sensing in mice, pigs and humans. Methods Mucosal biopsy samples taken at six locations in human intestine (n = 40) were analyzed by qPCR. Intestinal scrapings from 14 locations in pigs (n = 6) and from 10 locations in mice (n = 4) were analyzed by qPCR and microarray, respectively. The gene expression of glucagon, cholecystokinin, peptide YY, glucagon-like peptide-1 receptor, taste receptor T1R3, sodium/glucose cotransporter, peptide transporter-1, GPR120, taste receptor T1R1, GPR119 and GPR93 was investigated. Partial least squares (PLS) modeling was used to compare the intestinal expression pattern between the three species. Results and conclusion The studied genes were found to display specific expression patterns along the intestinal tract. PLS analysis showed a high similarity between human, pig and mouse in the expression of genes related to nutrient sensing in the distal ileum, and between human and pig in the colon. The gene expression pattern was most deviating between the species in the proximal intestine. Our results give new insights in interspecies similarities and provide new leads for translational research and models aiming to modulate food intake processes in man

Current and Future Drug Targets in Weight Management

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-HT2C 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

Nutrition to optimise human health—how to obtain physiological substantiation?

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 stressorsis 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

The role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite

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

Bioactive Components in Traditional Foods Aimed at Health Promotion : A Route to Novel Mechanistic Insights and Lead Molecules?

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