The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific ...knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.
Display omitted
•Hepatic fatty acid oxidation (FAO) is critical for liver physiology during starvation•Hepatic FAO suppresses adipose lipolysis and systemic catabolism•Upon fasting, loss of hepatic FAO induces Pparα target genes in the liver•A ketogenic diet induces severe lipolysis and lethality in hepatic FAO-deficient mice
Lee et al. have generated mice that lack mitochondrial long-chain fatty acid β-oxidation specifically in the liver. They report that these mice can survive a 24-hr fast but not a low-carbohydrate ketogenic diet. Surprisingly, whole-body energy expenditure is largely maintained due to increased peripheral catabolism.
The mammalian intestinal epithelium self-renews rapidly and homeostasis is preserved via tightly controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control ...different cell functions, but little is known about their role in maintaining the integrity of the intestinal epithelium. We searched for T-UCRs that regulate growth of the intestinal mucosa and investigated the mechanism by which T-UCR uc.173 regulates epithelial renewal.
C57BL/6J mice were deprived of food for 48 hours in fasting experiments. Some mice were given intraperitoneal injections of a plasmid encoding LNA-anti-uc.173, to knock down endogenous uc.173. For studies using organoids, primary enterocytes were isolated from the intestine and transfected with the uc.173 transgene to increase uc.173 levels. Intestinal epithelial cells (Caco-2 and IEC-6 lines) were transfected with LNA-anti-uc.173 or uc.173 transgene. We quantified intestinal epithelial renewal based on BrdU incorporation, villus height and crypt depth, and cell number. The association of uc.173 with microRNA 195 (miRNA195) was determined by RNA pull-down assays.
Genome-wide profile analyses identified 21 T-UCRs, including uc.173, that were differentially expressed between intestinal mucosa of fasted vs non-fasted mice. Increasing levels of uc.173 by expression of a transgene increased growth of intestinal epithelial cells and organoids. Decreasing uc.173 levels by LNA-anti-uc.173 in mice reduced renewal of the intestinal epithelium. We found that uc.173 interacted directly with the primary transcript of miRNA195, leading to miRNA195 degradation.
In analyses of intestinal epithelial cells and mice, we identified uc.173 noncoding RNA that regulates growth of the intestinal mucosa and stimulates intestinal epithelial renewal by reducing levels of miRNA195.
Display omitted
ROOTHAIRLESS (RHL) is a typical type of basic helix‐loop‐helix (bHLH) transcription factor (TF), which has been reported to participate in various aspects of plant growth and in response to stress. ...However, the functions of RHL subfamily members in moso bamboo (Phyllostachys edulis) remain unknown. In this study, we identified 14 bHLH genes (PeRHL1–PeRHL14) in moso bamboo. Phylogenetic tree and conserved motif analyses showed that PeRHLs were clustered into three clades. The expression analysis suggested that PeRHL4 was co‐expressed with PeTIP1‐1 and PePHT1‐1 in moso bamboo. Moreover, these three genes were all up‐regulated in moso bamboo under drought stress and phosphate starvation. Y1H, DLR and EMSA assays demonstrated that PeRHL4 could activate the expression of PeTIP1‐1 and PePHT1‐1. Furthermore, overexpression of PeRHL4 could increase both drought and phosphate starvation tolerance in transgenic rice, in which the expression of OsTIPs and OsPHT1s was significantly improved, respectively. Overall, our results indicated that drought stress and phosphate starvation could induce the expression of PeRHL4, which in turn activated downstream genes involved in water and phosphate transport. Collectively, our findings reveal that PeRHL4 acting as a positive regulator contributes to enhancing the tolerance of moso bamboo under drought stress and phosphate starvation.
Summary statement
Drought stress and phosphate starvation trigger intricate signalling networks that impact plant growth. This study presents PeRHL4 as a regulatory factor to activate downstream genes for water and phosphate transport, potentially bolstering the tolerance of moso bamboo under stresses.
Social isolation and loneliness have potent effects on public health
. Research in social psychology suggests that compromised sleep quality is a key factor that links persistent loneliness to ...adverse health conditions
. Although experimental manipulations have been widely applied to studying the control of sleep and wakefulness in animal models, how normal sleep is perturbed by social isolation is unknown. Here we report that chronic, but not acute, social isolation reduces sleep in Drosophila. We use quantitative behavioural analysis and transcriptome profiling to differentiate between brain states associated with acute and chronic social isolation. Although the flies had uninterrupted access to food, chronic social isolation altered the expression of metabolic genes and induced a brain state that signals starvation. Chronically isolated animals exhibit sleep loss accompanied by overconsumption of food, which resonates with anecdotal findings of loneliness-associated hyperphagia in humans. Chronic social isolation reduces sleep and promotes feeding through neural activities in the peptidergic fan-shaped body columnar neurons of the fly. Artificial activation of these neurons causes misperception of acute social isolation as chronic social isolation and thereby results in sleep loss and increased feeding. These results present a mechanistic link between chronic social isolation, metabolism, and sleep, addressing a long-standing call for animal models focused on loneliness
.
When cultivated under stress conditions, many plants and algae accumulate oil. The unicellular green microalga Chlamydomonas reinhardtii accumulates neutral lipids (triacylglycerols; TAGs) during ...nutrient stress conditions. Temporal changes in TAG levels in nitrogen (N)‐ and phosphorus (P)‐starved cells were examined to compare the effects of nutrient depletion on TAG accumulation in C. reinhardtii. TAG accumulation and fatty acid composition were substantially changed depending on the cultivation stage before nutrient starvation. Profiles of TAG accumulation also differed between N and P starvation. Logarithmic‐growth‐phase cells diluted into fresh medium showed substantial TAG accumulation with both N and P deprivation. N deprivation induced formation of oil droplets concomitant with the breakdown of thylakoid membranes. In contrast, P deprivation substantially induced accumulation of oil droplets in the cytosol and maintaining thylakoid membranes. As a consequence, P limitation accumulated more TAG both per cell and per culture medium under these conditions. To enhance oil accumulation under P deprivation, we constructed a P deprivation‐dependent overexpressor of a Chlamydomonas type‐2 diacylglycerol acyl‐CoA acyltransferase (DGTT4) using a sulphoquinovosyldiacylglycerol 2 (SQD2) promoter, which was up‐regulated during P starvation. The transformant strongly enhanced TAG accumulation with a slight increase in 18 : 1 content, which is a preferred substrate of DGTT4. These results demonstrated enhanced TAG accumulation using a P starvation–inducible promoter.
Whether dieting makes people fatter has been a subject of considerable controversy over the past 30 years. More recent analysis of several prospective studies suggest, however, that it is dieting to ...lose weight in people who are in the healthy normal range of body weight, rather than in those who are overweight or obese, that most strongly and consistently predict future weight gain. This paper analyses the ongoing arguments in the debate about whether repeated dieting to lose weight in normal‐weight people represents unsuccessful attempts to counter genetic and familial predispositions to obesity, a psychosocial reaction to the fear of fatness or that dieting per se confers risks for fatness and hence a contributing factor to the obesity epidemic. In addressing the biological plausibility that dieting predisposes the lean (rather than the overweight or obese) to regaining more body fat than what had been lost (i.e. fat overshooting), it integrates the results derived from the re‐analysis of body composition data on fat mass and fat‐free mass (FFM) losses and recoveries from human studies of experimental energy restriction and refeeding. These suggest that feedback signals from the depletion of both fat mass (i.e. adipostats) and FFM (i.e. proteinstats) contribute to weight regain through the modulation of energy intake and adaptive thermogenesis, and that a faster rate of fat recovery relative to FFM recovery (i.e. preferential catch‐up fat) is a central outcome of body composition autoregulation in lean individuals. Such a temporal desynchronization in the restoration of the body's fat vs. FFM results in a state of hyperphagia that persists beyond complete recovery of fat mass and interestingly until FFM is fully recovered. However, as this completion of FFM recovery is also accompanied by fat deposition, excess fat accumulates. In other words, fat overshooting is a prerequisite to allow complete recovery of FFM. This confers biological plausibility for post‐dieting fat overshooting – which through repeated dieting and weight cycling would increase the risks for trajectories from leanness to fatness. Given the increasing prevalence of dieting in normal‐weight female and male among young adults, adolescents and even children who perceive themselves as too fat (due to media, family and societal pressures), together with the high prevalence of dieting for optimizing performance among athletes in weight‐sensitive sports, the notion that dieting and weight cycling may be predisposing a substantial proportion of the population to weight gain and obesity deserves greater scientific scrutiny.
The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal ...roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.
Glucose‐oxidase (GOx)‐mediated starvation by consuming intracellular glucose has aroused extensive exploration as an advanced approach for tumor treatment. However, this reaction of catalytic ...oxidation by GOx is highly dependent on the on‐site oxygen content, and thus starvation therapy often suffers unexpected anticancer outcomes due to the intrinsic tumorous hypoxia. Herein, porous platinum nanospheres (pPts), incorporated with GOx molecules (PtGs), are synthesized to enable synergistic cancer therapy. In this system, GOx can effectively catalyze the oxidation of glucose to generate H2O2, while pPt triggers the decomposition of both endogenous and exogenous H2O2 to produce considerable content of O2 to facilitate the glucose consumption by GOx. Meanwhile, pPt induces remarkable content of intracellular reactive oxygen species (ROS) under an alternating electric field, leading to cellular oxidative stress injury and promotes apoptosis following the mechanism of electrodynamic therapy (EDT). In consequence, the PtG nanocomposite exhibits significant anticancer effect both in vitro and in vivo. This study has therefore demonstrated a fascinating therapeutic platform enabling oxygen‐inductive starvation/EDT synergistic strategy for effective tumor treatment.
Porous platinum nanospheres (pPts) incorporated with glucose oxidase (GOx) molecules (PtGs) are synthesized for synergistic electrodynamic/starvation therapy. Despite its feasible loading for GOx, pPt enables sufficient O2 supply to facilitate GOx‐mediated starvation by decomposing H2O2. Meanwhile, PtG induces reactive oxygen species (ROS) under an electric field following an electrodynamic mechanism. Considerable in vitro and in vivo tumor inhibition is consequently achieved.
PDF
