ABSTRACT
Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adiposity/genetics , Fatty Acids/metabolism , Metabolic Diseases/genetics , Muscle, Skeletal/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Gene Expression Regulation , Insulin Resistance/genetics , Male , Metabolic Diseases/metabolism , Mice, Inbred C57BL , Mice, Knockout , Obesity/genetics , Obesity/metabolism , Oxidation-Reduction , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction/methods , YAP-Signaling ProteinsABSTRACT
A growing body of evidence from research in rodents and humans has identified insulin as an important neuoregulatory peptide in the brain, where it coordinates diverse aspects of energy balance and peripheral glucose homeostasis. This review discusses where and how insulin interacts within the brain and evaluates the physiological and pathophysiological consequences of central insulin signalling in metabolism, obesity and type 2 diabetes.
Subject(s)
Brain/metabolism , Energy Metabolism , Glucose/metabolism , Insulin/metabolism , Adiposity , Animals , Body Weight , Diabetes Mellitus, Type 2 , Feeding Behavior , Humans , Insulin Resistance , Metabolic Diseases/metabolism , ObesityABSTRACT
Endocannabinoids have a variety of effects by acting through cannabinoid 1 (CB1) receptors located throughout the brain. However, since CB1 receptors are located presynaptically, and because the strength of downstream coupling varies with brain region, expression studies alone do not provide a firm basis for interpreting sites of action. Likewise, to date most functional studies have used high doses of drugs, which can bias results toward non-relevant adverse effects, and which mask more behaviourally-relevant actions. Here we use a low, orexigenic dose of the full CB1 agonist, CP55940, to map responsive brain regions using the complementary techniques of pharmacological-challenge functional magnetic resonance imaging (phMRI) and immediate-early gene activity. Areas of interest demonstrate a drug interaction when the CB1 receptor inverse agonist, rimonabant, is co-administered. This analysis highlights the corticostriatal-hypothalamic pathway, which is central to the motivational drive to eat.
