Modeling Energy Dynamics in Mice with Skeletal Muscle Hypertrophy Fed High Calorie Diets.

Retrospective and prospective studies show that lean mass or strength is positively associated with metabolic health. Mice deficient in myostatin, a growth factor that negatively regulates skeletal muscle mass, have increased muscle and body weights and are resistant to diet-induced obesity. Their leanness is often attributed to higher energy expenditure in the face of normal food intake. However, even obese animals have an increase in energy expenditure compared to normal weight animals suggesting this is an incomplete explanation. We have previously developed a computational model to estimate energy output, fat oxidation and respiratory quotient from food intake and body composition measurements to more accurately account for changes in body composition in rodents over time. Here we use this approach to understand the dynamic changes in energy output, intake, fat oxidation and respiratory quotient in muscular mice carrying a dominant negative activin receptor IIB expressed specifically in muscle. We found that muscular mice had higher food intake and higher energy output when fed either chow or a high-fat diet for 15 weeks compared to WT mice. Transgenic mice also matched their rate of fat oxidation to the rate of fat consumed better than WT mice. Surprisingly, when given a choice between high-fat diet and Ensure® drink, transgenic mice consumed relatively more calories from Ensure® than from the high-fat diet despite similar caloric intake to WT mice. When switching back and forth between diets, transgenic mice adjusted their intake more rapidly than WT to restore normal caloric intake. Our results show that mice with myostatin inhibition in muscle are better at adjusting energy intake and output on diets of different macronutrient composition than WT mice to maintain energy balance and resist weight gain.

Increasing muscle mass to improve metabolism.

Skeletal muscle insulin resistance is a predictor of the development of type 2 diabetes and maintenance of adequate muscle glucose disposal in muscle may help to prevent diabetes. Lipodystrophy is a type of diabetes caused by a reduction of white adipose tissue and the adipokine leptin. Lipidemia, insulin resistance and hyperphagia develop as a consequence. In a recent study, we showed that increasing skeletal muscle mass by inhibiting signaling of myostatin, a transforming growth factor ß (TGFß) family member that negatively regulates muscle growth, prevents the development of diabetes in a mouse model of lipodystrophy. Muscle-specific myostatin inhibition also prevented hyperphagia suggesting muscle may regulate food intake. Here we discuss these results in the context of strategies to increase muscle insulin sensitivity as well as new findings about the effects of myostatin and other TGFß family members on similar metabolic processes.

Myostatin inhibition prevents diabetes and hyperphagia in a mouse model of lipodystrophy.

Lipodystrophies are characterized by a loss of white adipose tissue, which causes ectopic lipid deposition, peripheral insulin resistance, reduced adipokine levels, and increased food intake (hyperphagia). The growth factor myostatin (MSTN) negatively regulates skeletal muscle growth, and mice with MSTN inhibition have reduced adiposity and improved insulin sensitivity. MSTN inhibition may therefore be efficacious in ameliorating diabetes. To test this hypothesis, we inhibited MSTN signaling in a diabetic model of generalized lipodystrophy to analyze its effects on glucose metabolism separate from effects on adipose mass. A-ZIP/F1 lipodystrophic mice were crossed to mice expressing a dominant-negative MSTN receptor (activin receptor type IIB) in muscle. MSTN inhibition in A-ZIP/F1 mice reduced blood glucose, serum insulin, triglyceride levels, and the rate of triglyceride synthesis, and improved insulin sensitivity. Unexpectedly, hyperphagia was normalized by MSTN inhibition in muscle. Blood glucose and hyperphagia were reduced in double mutants independent of the adipokine leptin. These results show that the effect of MSTN inhibition on insulin sensitivity is not secondary to an effect on adipose mass and that MSTN inhibition may be an effective treatment for diabetes. These results further suggest that muscle may play a heretofore unappreciated role in regulating food intake.

ßFTZ-F1 and Matrix metalloproteinase 2 are required for fat-body remodeling in Drosophila.

During metamorphosis, holometabolous insects eliminate obsolete larval tissues via programmed cell death. In contrast, tissues required for further development are retained and often remodeled to meet the needs of the adult fly. The larval fat body is involved in fueling metamorphosis, and thus it escapes cell death and is instead remodeled during prepupal development. The molecular mechanisms by which the fat body escapes programmed cell death have not yet been described, but it has been established that fat-body remodeling requires 20-hydroxyecdysone (20E) signaling. We have determined that 20E signaling is required within the fat body for the cell-shape changes and cell detachment that are characteristic of fat-body remodeling. We demonstrate that the nuclear hormone receptor ßFTZ-F1 is a key modulator of 20E hormonal induction of fat body remodeling and Matrix metalloproteinase 2 (MMP2) expression in the fat body. We show that induction of MMP2 expression in the fat body requires 20E signaling, and that MMP2 is necessary and sufficient to induce fat-body remodeling.

The role of 20-hydroxyecdysone signaling in Drosophila pupal metabolism.

In holometabolous insects, the steroid hormone 20-hydroxyecdysone (20E), in coordination with juvenile hormone, regulates the major developmental events that promote larval development and the transition from the larval to the pupal stage. Intimately entwined with the hormonal control of development is the control of larval growth and the acquisition of energy stores necessary for the development of the non-feeding pupa and immature adult. Studies of the coordination of insect development and growth have suggested that the larval fat body plays a central role in monitoring animal size and nutritional status by integrating 20E signaling with the insulin signaling pathway. Previous studies have shown that tissue-specific loss of 20E signaling in the fat body causes pupal lethality (Cherbas et al., 2003). Because the fat body is the major organ responsible for nutrient homeostasis, we hypothesized that the observed pupal mortality is due to a metabolic defect. In this paper we show that disruption of 20E signaling in the fat body does not disrupt nutrient storage, animal size at pupariation, or nutrient utilization. We conclude that 20E signaling in the fat body is not necessary for normal pupal metabolism.