MCI is associated with changes in white matter and subcortical regions as seen on DTI. Changes in some anterior brain regions distinguish aMCI from naMCI.
Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. “Diversity Outbred in Australia (DOz)” is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle’s contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focussing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform andin vitroassays of insulin action using the Prestwick chemical library. These complimentary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation inex vivoinsulin resistant mouse muscle, and palmitate induced insulin resistant myotubes demonstrated potent insulin action restoration, potentially via up-regulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems level analysis by identifying potential therapeutics for insulin resistance.
The pattern of weight loss and regain, termed "weight cycling," is common in overweight individuals. It is unclear whether the well-established benefits of weight loss persist following weight regain or whether weight cycling is harmful. Human studies of weight cycling have conflicting results reflecting limitations of the observational designs of these studies. By controlling the macronutrient content of diets in animal studies, weight cycling can be studied in a highly controlled manner, thereby overcoming the limitations of human studies. We conducted a systematic review and meta-analysis of animal studies which assessed the health consequences of weight cycling. Studies were classified into those which compared weight cycling to lifelong obesity and those which compared weight cycling to later onset obesity. There were no differences in health outcomes between weight cycled animals and those with lifelong obesity, highlighting that weight regain reverses health benefits achieved by weight loss. In comparison with animals with later onset obesity, weight cycled animals had higher fasting glucose levels and more impaired glucose tolerance following weight regain. Our review of animal studies suggests that health benefits of diet-induced weight loss do not persist after weight regain and weight cycling results in adverse metabolic outcomes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.