ABSTRACT
Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.
Subject(s)
Activin Receptors, Type II/antagonists & inhibitors , Adipogenesis/physiology , Adipose Tissue, Brown/metabolism , Thermogenesis/physiology , Activin Receptors, Type II/immunology , Activin Receptors, Type II/metabolism , Adipocytes, Brown/cytology , Adipocytes, Brown/metabolism , Adipose Tissue, Brown/ultrastructure , Animals , Antibodies, Neutralizing , Cell Differentiation , Energy Metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mice, SCID , Mice, Transgenic , Microscopy, Electron, Transmission , Mitochondria/metabolism , Muscle, Skeletal/metabolism , Myostatin/metabolism , Signal Transduction , Smad3 Protein/metabolism , Transcription Factors/metabolismABSTRACT
Maximal exercise performance is a multifactorial process in which the cardiovascular component, the innervation of the musculature, and the contractile and metabolic properties of skeletal muscle all play key roles. Here, protocols are provided for assessment of maximal running capacity of mice on a treadmill, with a combination of short high-intensity paradigms primarily intended to test for maximal power and cardiovascular function, and longer low-intensity paradigms to assess endurance and oxidative metabolism in skeletal muscle. The coupling of treadmill running to indirect calorimetry, to correlate performance measurements to maximal oxygen consumption, is also described. Curr. Protoc. Mouse Biol. 1:141-154. © 2011 by John Wiley & Sons, Inc.
ABSTRACT
The locomotor activity of laboratory mice is a global behavioral trait which can be valuable for the primary phenotyping of genetically engineered mouse models as well as mouse models of pathologies affecting the central and peripheral nervous systems, the musculoskeletal system, and the control of energy homeostasis. Basal levels of mouse locomotion can be recorded using infrared monitoring of movements, and further information can be gathered by giving the animal access to a running wheel, which will greatly enhance its spontaneous physical activity. Described here are two detailed protocols to evaluate basal locomotor activity and spontaneous wheel running. Curr. Protoc. Mouse Biol. 1:185-198. © 2011 by John Wiley & Sons, Inc.