Biology subjects

Harvey, I.

Publications and source records attributed to Harvey, I..

3 recordsLinked to original sources

bioRxiv2020

Obesity promotes glucocorticoid-dependent muscle atrophy in male C57BL/6J mice.

Glucocorticoids promote muscle atrophy by inducing a class of proteins called atrogenes, resulting in reductions in muscle size and strength. In this work, we evaluated whether a mouse model with pre-existing diet-induced obesity had altered glucocorticoid responsiveness. We observed that all animals treated with the synthetic glucocorticoid dexamethasone had reduced strength, but that obesity exacerbated this effect. These changes were concordant with more pronounced reductions in muscle size, particularly in Type II muscle fibers, and potentiated induction of atrogene expression in the obese mice relative to lean mice. Furthermore, we show that the reductions in lean mass do not fully account for the dexamethasone-induced insulin resistance observed in these mice. Together these data suggest that obesity potentiates glucocorticoid-induced muscle atrophy.

physiology↗

bioRxiv2019

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

physiology↗

bioRxiv2017

Glucocorticoid-Induced Metabolic Disturbances are Exacerbated in Obesity

Obesity and chronically elevated glucocorticoids result in similar co-morbidities, but the effect of a combination of these ailments on metabolic outcomes is unclear. Measures of glucose homeostasis and markers of hepatic lipid accumulation were assessed to determine whether obesity exaggerated the effects of dexamethasone-induced metabolic disturbances. The combination of obesity and glucocorticoids resulted in hepatic steatosis and synergistic impairments in insulin sensitivity and this was matched with synergistic elevations in markers of lipolysis. These findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in people with obesity.

physiology↗