The H2020 “NoHoW Project”: A Position Statement on Behavioural Approaches to Longer-Term Weight Management

There is substantial evidence documenting the effects of behavioural interventions on weight loss (WL). However, behavioural approaches to initial WL are followed by some degree of longer-term weight regain, and large trials focusing on evidence-based approaches to weight loss maintenance (WLM) have generally only demonstrated small beneficial effects. The current state-of-the-art in behavioural interventions for WL and WLM raises questions of (i) how we define the relationship between WL and WLM, (ii) how energy balance (EB) systems respond to WL and influence behaviours that primarily drive weight regain, (iii) how intervention content, mode of delivery and intensity should be targeted to keep weight off, (iv) which mechanisms of action in complex interventions may prevent weight regain and (v) how to design studies and interventions to maximise effective longer-term weight management. In considering these issues a writing team within the NoHoW Consortium was convened to elaborate a position statement, and behaviour change and obesity experts were invited to discuss these positions and to refine them. At present the evidence suggests that developing the skills to self-manage EB behaviours leads to more effective WLM. However, the effects of behaviour change interventions for WL and WLM are still relatively modest and our understanding of the factors that disrupt and undermine self-management of eating and physical activity is limited. These factors include physiological resistance to weight loss, gradual compensatory changes in eating and physical activity and reactive processes related to stress, emotions, rewards and desires that meet psychological needs. Better matching of evidence-based intervention content to quantitatively tracked EB behaviours and the specific needs of individuals may improve outcomes. Improving objective longitudinal tracking of energy intake and energy expenditure over time would provide a quantitative framework in which to understand the dynamics of behaviour change, mechanisms of action of behaviour change interventions and user engagement with intervention components to potentially improve weight management intervention design and evaluation

A Combination of Nutriments Improves Mitochondrial Biogenesis and Function in Skeletal Muscle of Type 2 Diabetic Goto–Kakizaki Rats

BACKGROUND: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-alpha (Ppar alpha), peroxisome proliferator-activated receptor-delta (Ppar delta), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. CONCLUSIONS/SIGNIFICANCE: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain

Prediction of Promiscuous P-Glycoprotein Inhibition Using a Novel Machine Learning Scheme

BACKGROUND: P-glycoprotein (P-gp) is an ATP-dependent membrane transporter that plays a pivotal role in eliminating xenobiotics by active extrusion of xenobiotics from the cell. Multidrug resistance (MDR) is highly associated with the over-expression of P-gp by cells, resulting in increased efflux of chemotherapeutical agents and reduction of intracellular drug accumulation. It is of clinical importance to develop a P-gp inhibition predictive model in the process of drug discovery and development. METHODOLOGY/PRINCIPAL FINDINGS: An in silico model was derived to predict the inhibition of P-gp using the newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme based on the data compiled from the literature. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those structurally diverse molecules in the training set (n = 31, r(2) = 0.89, q(2) = 0.86, RMSE = 0.40, s = 0.28), the test set (n = 88, r(2) = 0.87, RMSE = 0.39, s = 0.25) and the outlier set (n = 11, r(2) = 0.96, RMSE = 0.10, s = 0.05). The generated PhE/SVM model also showed high accuracy when subjected to those validation criteria generally adopted to gauge the predictivity of a theoretical model. CONCLUSIONS/SIGNIFICANCE: This accurate, fast and robust PhE/SVM model that can take into account the promiscuous nature of P-gp can be applied to predict the P-gp inhibition of structurally diverse compounds that otherwise cannot be done by any other methods in a high-throughput fashion to facilitate drug discovery and development by designing drug candidates with better metabolism profile

The maternal microbiome during pregnancy and allergic disease in the offspring

There is substantial epidemiological and mechanistic evidence that the increase in allergic disease and asthma in many parts of the world in part relates to changes in microbial exposures and diet acting via the composition and metabolic products of the intestinal microbiome. The majority of research in this field has focused on the gut microbiome during infancy, but it is increasingly clear that the maternal microbiome during pregnancy also has a key role in preventing an allergy-prone immune phenotype in the offspring. The mechanisms by which the maternal microbiome influences the developing fetal immune system include alignment between the maternal and infant regulatory immune status and transplacental passage of microbial metabolites and IgG. Interplay between microbial stimulatory factors such as lipopolysaccharides and regulatory factors such as short-chain fatty acids may also influence on fetal immune development. However, our understanding of these pathways is at an early stage and further mechanistic studies are needed. There are also no data from human studies relating the composition and metabolic activity of the maternal microbiome during pregnancy to the offspring's immune status at birth and risk of allergic disease. Improved knowledge of these pathways may inform novel strategies for tackling the increase in allergic disorders in the modern world