mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3.

OBJECTIVE: We have recently shown that acute inhibition of both mTOR complexes (mTORC1 and mTORC2) increases whole-body lipid utilization, while mTORC1 inhibition had no effect. Therefore, we tested the hypothesis that mTORC2 regulates lipid metabolism in skeletal muscle. METHODS: Body composition, substrate utilization and muscle lipid storage were measured in mice lacking mTORC2 activity in skeletal muscle (specific knockout of RICTOR (Ric mKO)). We further examined the RICTOR/mTORC2-controlled muscle metabolome and proteome; and performed follow-up studies in other genetic mouse models and in cell culture. RESULTS: Ric mKO mice exhibited a greater reliance on fat as an energy substrate, a re-partitioning of lean to fat mass and an increase in intramyocellular triglyceride (IMTG) content, along with increases in several lipid metabolites in muscle. Unbiased proteomics revealed an increase in the expression of the lipid droplet binding protein Perilipin 3 (PLIN3) in muscle from Ric mKO mice. This was associated with increased AMPK activity in Ric mKO muscle. Reducing AMPK kinase activity decreased muscle PLIN3 expression and IMTG content. AMPK agonism, in turn, increased PLIN3 expression in a FoxO1 dependent manner. PLIN3 overexpression was sufficient to increase triglyceride content in muscle cells. CONCLUSIONS: We identified a novel link between mTORC2 and PLIN3, which regulates lipid storage in muscle. While mTORC2 is a negative regulator, we further identified AMPK as a positive regulator of PLIN3, which impacts whole-body substrate utilization and nutrient partitioning

Fetal growth and later maternal death, cardiovascular disease and diabetes

Low birthweight of the offspring has been associated with increased risk of early death and ischemic heart disease in the mother. However, other measurements of fetal growth than the basic birthweight are more accurate. We investigated the relation between the standardized birthweight by gestational age and gender and the ponderal index and the mother's subsequent mortality and cardiovascular morbidity. Registry-based retrospective cohort study. Women with a first singleton delivery in Denmark from 1978 to 2007. 782 287 women followed for 14.6 years yielding 11 600 945 person-years. Cox proportional hazard models. The primary exposures were variation in the standardized birthweight and ponderal index. The endpoints were subsequent maternal death, hypertension, ischemic heart disease, stroke, thrombosis, and diabetes mellitus. The risk-profile for the standardized birthweight and subsequent maternal death had a nadir between -0.5 and -1 SD (HR 0.91; 95%CI 0.83-1.00) and increased with decreasing fetal growth peaking at +3 SD (HR 17.8; 95%CI 15.0-21.0). The risk-profiles for standardized ponderal index paralleled those for birthweight, but with smaller risk estimates. Adjusting for other pregnancy complications diminished the estimates. The fetal growth is a marker of subsequent risk for premature death, cardiovascular disease, and diabetes mellitus in the mother

Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study.

BackgroundPeripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM.MethodsUsing nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity.ResultsIn a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0-37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18-16.9; gestational hypertension, RR 5.16, 95% CI 2.11-12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02).ConclusionsAlthough 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart's capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy