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The timing of food intake is a novel dietary component that can impact health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. During pregnancy, one may experience disruptions to food intake for diverse reasons (e.g. nausea and vomiting of pregnancy, food insecurity, desire to manage gestational weight gain, disordered eating behaviors, changes in taste and food preferences, etc) and therefore may experience periods of intentional or unintentional fasting similar to TRF protocols. Because interest in TRF is gaining popularity and feeding may be interrupted in those who are pregnant, it is important to understand the long-term effects of TRF during pregnancy on the resultant offspring. Using a mouse model, we tested the effects of gestational exposure to early TRF (eTRF) over the life course of both male and female offspring. Offspring body composition was similar between experimental groups in both males and females from weaning (day 21) to adulthood (day 70), with minor increases in food intake in eTRF females and improved glucose tolerance in males. After 10 weeks of high fat, high sucrose diet feeding, male eTRF offspring were more sensitive to insulin but developed glucose intolerance with impaired insulin secretion. As such, gestational eTRF causes sex-specific deleterious effects on glucose homeostasis after chronic high fat, high sucrose diet feeding in male offspring. Further studies are needed to determine the effect gestational eTRF has on the male pancreas as well as to elucidate the mechanisms that protect females from this metabolic dysfunction.

Insulin tolerance tests are a standard and common method for evaluating the insulin sensitivity of an animal. In this assay, animals are fasted to normalize blood glucose and then challenged by an intraperitoneal injection of insulin. As glucose is transported into tissues and glucose production is suppressed, glucose levels drop. A more insulin sensitive animal will have a larger decrease in blood glucose. This has advantages over a glucose tolerance test which measures both insulin sensitivity and insulin responsiveness.

Time-Restricted Feeding (TRF) is an increasingly common diet that may improve insulin sensitivity. This practice merits study in the setting of pregnancy, as the diet is common, pregnancy represents a critical period for the health of both mother and offspring, and the effects of TRF during pregnancy on maternal gestational health and long-term offspring consequences remain unexamined. To test these effects, female mice were randomized to 6 hours of food availability in the dark cycle (early-time restricted feeding, eTRF), or given 24-hour ad libitum (AL) food access. After one week of acclimatization, females were mated. Food intake and body composition were measured weekly throughout gestation; insulin sensitivity was assessed at day 16 of pregnancy. Offspring birth rate, survival, birthweight, and gestational age were assessed. Body composition and food intake were assessed weekly. After 70 days on a normal diet, all offspring were switched to a 45% high-fat diet (HFD) with continued weekly monitoring. Glucose tolerance and insulin tolerance tests were conducted before and after 10 weeks of HFD feeding. Our data suggests that maternal eTRF does not affect birth weight or gestational age, but does reduce litter size (7.7 pups vs. 6.0 pups) and 3-day pup survival (95% vs. 58%) compared to AL. eTRF offspring had similar insulin and glucose tolerance compared to AL counterparts until adulthood (70 days of age). After 12 weeks of high-fat diet feeding, eTRF males develop concomitant glucose intolerance (auc, p Disclosure M. E. Carter: None. N. El habbal: None. D. S. Snyder: None. J. R. Redd: None. B. Gregg: None. D. Bridges: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107535); University of Michigan

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.

The placenta is the primary organ responsible for deactivating maternal glucocorticoids and reducing fetal exposure. Glucocorticoid use during pregnancy is a common treatment for asthma, allergies, and COVID-19. Several studies have reported adverse effects including intrauterine growth restriction as a result of glucocorticoid exposure, yet little is known about the mechanisms by which short and long-term maternal glucocorticoid exposures affect placental biology and fetal development. To better understand the role of glucocorticoids on placental and fetal outcomes, we used a mouse model exposed to the synthetic glucocorticoid, dexamethasone (Dex), prior to and throughout gestation. We conducted a randomized controlled trial in mice with a treatment arm of Dex exposure and water exposure as control. Virgin C57Bl/6J female mice were single-housed at 11 weeks of age, and Dex was introduced in the drinking water as a 1mg/kg/day dose. After one week of treatment, mice were bred with age-matched virgin males. Dam body composition, food, and water intake were monitored weekly. Maternal insulin sensitivity, pup survival rate, litter size, and pup birth weight at postnatal day (PND) 0.5 were also assessed. Dams treated with Dex lost significant lean mass after one week of treatment. Dex treatment did not appear to affect the dams’ ability to get pregnant, as both groups carried pups to term with similar lengths of gestation (p=0.838). Water and Dex-treated dams gained comparable weight during the first and second trimesters of pregnancy, however, the Dex group gained less lean mass than the water group during the third trimester. At PND0.5, Dex dams had fewer pups with a 40% reduction in litter size (p=0.01) and lighter pups with a 37% reduction in offspring weight (p

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.

We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle.

The purpose of this study was to determine the effects of glucocorticoid-induced metabolic dysfunction in the presence of diet-induced obesity. C57BL/6J adult male lean and diet-induced obese mice were given dexamethasone, and levels of hepatic steatosis, insulin resistance, and lipolysis were determined. Obese mice given dexamethasone had significant, synergistic effects on fasting glucose, insulin resistance, and markers of lipolysis, as well as hepatic steatosis. This was associated with synergistic transactivation of the lipolytic enzyme adipose triglyceride lipase. The combination of chronically elevated glucocorticoids and obesity leads to exacerbations in metabolic dysfunction. Our findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in individuals with obesity.

Objective: To determine the effects of glucocorticoid-induced metabolic dysfunction in the presence of diet-induced obesity. Methods: C57BL/6J adult male lean and diet-induced obese mice were given dexamethasone for different durations and levels of hepatic steatosis, insulin resistance and lipolysis were determined. Results: Obese mice given dexamethasone had significant, synergistic effects on insulin resistance and markers of lipolysis, as well as hepatic steatosis. This was associated with synergistic transactivation of the lipolytic enzyme ATGL. Conclusions: The combination of chronically elevated glucocorticoids and obesity leads to exacerbations in metabolic dysfunction. Our findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in individuals with obesity.

Myogenesis is an important process during both development and muscle repair. Previous studies suggest that mTORC1 plays a role in the formation of mature muscle from immature muscle precursor cells. Here we show that gene expression for several myogenic transcription factors including Myf5, Myog and Mef2c but not MyoD and myosin heavy chain isoforms decrease when C2C12 cells are treated with rapamycin, supporting a role for mTORC1 pathway during muscle development. To investigate the possibility that mTORC1 can regulate muscle in vivo we ablated the essential dTORC1 subunit Raptor in Drosophila melanogaster and found that muscle-specific knockdown of Raptor causes flies to be too weak to emerge from their pupal cases during eclosion. Using a series of GAL4 drivers we also show that muscle-specific Raptor knockdown also causes shortened lifespan, even when eclosure is unaffected. Together these results highlight an important role for TORC1 in muscle development, integrity and function in both Drosophila and mammalian cells.