How muscle communicates nutritional status to regulate physiologic homeostasis

skeletal muscle;myokine;CTRP15;Fam132b;myonectin;fatty acid uptake;glucose metabolism;liver function;autophagy;mTOR;Akt;not listed

Seldin, MarcusWatkins, Paul A. ;

Johns Hopkins University

关键词: skeletal muscle;    myokine;    CTRP15;    Fam132b;    myonectin;    fatty acid uptake;    glucose metabolism;    liver function;    autophagy;    mTOR;    Akt;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37149/SELDIN-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The integrated control of animal and human physiology requires intimate tissue crosstalk, a vital task mediated by circulating humoral factors.The recent realization that skeletal muscle, the largest organ in the human body, secretes a variety of biologically and metabolically active polypeptide factors (collectively called myokines) has provided a new conceptual framework to understand the coordination of whole-body physiology and energy balance.Here we report the identification and functional characterization of myonectin, the first skeletal muscle-specific secreted protein which links this critical organ to postprandial metabolic homeostasis.In mouse models we show myonectin mRNA and protein is suppressed with fasting, but dramatically induced upon nutrient availability.Further, myonectin exerts significant control over regulating whole-body glucose and fat metabolism through novel endocrine circuitry.Myonectin acts in a postprandial mechanism to reduce circulating lipid levels.This reduction is facilitated by enhanced expression of fatty-acid uptake genes in both adipose tissue and liver.Additionally, myonectin significantly reduces blood glucose levels by inhibiting glucose output, while simultaneously promoting uptake and deposition into liver. Given the dependence of myonectin expression on nutrient homeostasis, we further explored how the protein regulates hepatic autophagy, an important process in regulating metabolic fuels.Myonectin significantly reduced both acute and chronic liver autophagic functions by activating the well-described PI3Kinase/Akt/mTOR pathway. Our data suggests myonectin functions as a skeletal muscle nutrient sensor, which communicates the status of muscle energy reserves to other metabolically relevant organs.Given the important contribution of skeletal muscle (comprising ~40% of total body mass) to whole-body metabolism, these studies yield novel and fundamental insights into how myonectin links skeletal muscle to energy regulation in muscle and non-muscle tissues.This basic knowledge can be utilized in a therapeutic setting to approach and treat Type 2 diabetes, obesity and other metabolic perturbations.