Explore the vast range of titles available.

Alternative route to fatty acids Oxidative metabolism of glucose has long been considered to be the major provider of carbon for lipid synthesis in animal cells. Two papers in this issue of Nature demonstrate that reductive carboxylation of glutamine is an alternative. Metallo et al . show that various normal and cancerous human cell lines proliferating in hypoxic conditions produce the acetyl-coenzyme A required as a precursor for fatty acid synthesis by the reductive metabolism of glutamine-derived α-ketoglutarate through a pathway requiring isocitrate dehydrogenase 1. Mullen et al . show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation as the major pathway of citrate formation. As well as adding a new dimension to our understanding of cell carbohydrate metabolism, this work suggests that there may be potential therapeutic targets along the reductive carboxylation and glutamine catabolic pathways that could prevent hypoxic tumour growth. Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol 1 , 2 , 3 . However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis 4 . Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis 5 , the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel–Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.

Lipid metabolism in obesity The function of the endoplasmic reticulum (ER) changes during obesity: in the liver, ER-associated protein synthesis slows down, and genes involved in lipid metabolism are switched on. ER stress is an important factor in obesity, insulin resistance and type 2 diabetes. A possible mechanism for this link has now been identified. Perturbation of fatty acid and lipid metabolism in the ER inhibits the activity of SERCA, the main ER calcium importer. Changing the lipid composition or increasing the amount of SERCA in the ER is shown to relieve the stress and improve glucose homeostasis in vivo . The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response 1 . Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity 2 . However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome. Lipid droplets and autophagy Lipid droplets are cytoplasmic organelles that store lipids such as triglycerides and cholesterol. Under conditions of nutrient deprivation, droplet triglycerides are hydrolysed to generate free fatty acids that are oxidized to provide energy. A second cellular response to starvation is autophagy, in which the cell digests its own components to provide nutrients. Singh et al . describe a novel function for autophagy in regulating lipid metabolism, which they term 'macrolipophagy'. In this process, lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. Autophagy promotes lipid hydrolysis and generation of free fatty acids by releasing the content of lipid droplets to lysosomes for degradation. This work identifies a critical role of autophagy in regulating lipid metabolism and may provide a new approach to the prevention of lipid accumulation in disease. Description of a novel function for autophagy in regulating lipid metabolism, called 'macrolipophagy', in which lipid droplets and autophagic components associate during starvation and inhibition of autophagy increases lipid storage in lipid droplets. A critical role of autophagy in regulating lipid metabolism is identified, and may provide a new approach to prevent lipid accumulation in disease.

Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.

Fibroblast growth factor (FGF) 19 is an enterokine synthesized and released when bile acids are taken up into the ileum. We show that FGF19 stimulates hepatic protein and glycogen synthesis but does not induce lipogenesis. The effects of FGF19 are independent of the activity of either insulin or the protein kinase Akt and, instead, are mediated through a mitogen-activated protein kinase signaling pathway that activates components of the protein translation machinery and stimulates glycogen synthase activity. Mice lacking FGF15 (the mouse FGF19 ortholog) fail to properly maintain blood concentrations of glucose and normal postprandial amounts of liver glycogen. FGF19 treatment restored the loss of glycogen in diabetic animals lacking insulin. Thus, FGF19 activates a physiologically important, insulin-independent endocrine pathway that regulates hepatic protein and glycogen metabolism.

Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.

A bilayer material comprising catalyst-bearing microstructures embedded in a responsive gel and actuated into and out of a reactant-containing ‘nutrient’ layer continuously interconverts chemical, thermal and mechanical energy and thereby shows autonomous, self-sustained homeostatic behaviour, which regulates the temperature of the system in a narrow range. Flexible materials: get SMARTS Taking their cue from the ability of living organisms to maintain control over their local environment through homeostasis, Joanna Aizenberg and colleagues have developed a way to produce synthetic homeostatic materials that autonomously regulate a wide range of parameters at the micrometre scale through a series of chemo-mechanical feedback loops. They describe a bilayer of hydrogel-supported catalyst-bearing microstructures separated from a reactant-containing 'nutrient' layer. Reconfiguration of the gel in response to a stimulus induces reversible actuation of the microstructures in and out of the nutrient layer, and serves as an on/off switch for chemical reactions — a sort of artificial homeostasis. This design triggers organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles that are synchronized with the motion of the microstructures and the driving external chemical stimulus. The authors suggest that SMARTS (self-regulated mechano-chemical adaptively reconfigurable tunable systems) could be tailored to modulate variables such as light, pH, glucose, pressure and oxygen. Applications might include robotics, biomedical engineering and building materials. Living organisms have unique homeostatic abilities, maintaining tight control of their local environment through interconversions of chemical and mechanical energy and self-regulating feedback loops organized hierarchically across many length scales 1 , 2 , 3 , 4 , 5 , 6 , 7 . In contrast, most synthetic materials are incapable of continuous self-monitoring and self-regulating behaviour owing to their limited single-directional chemomechanical 7 , 8 , 9 , 10 , 11 , 12 or mechanochemical 13 , 14 modes. Applying the concept of homeostasis to the design of autonomous materials 15 would have substantial impacts in areas ranging from medical implants that help stabilize bodily functions to ‘smart’ materials that regulate energy usage 2 , 16 , 17 . Here we present a versatile strategy for creating self-regulating, self-powered, homeostatic materials capable of precisely tailored chemo-mechano-chemical feedback loops on the nano- or microscale. We design a bilayer system with hydrogel-supported, catalyst-bearing microstructures, which are separated from a reactant-containing ‘nutrient’ layer. Reconfiguration of the gel in response to a stimulus induces the reversible actuation of the microstructures into and out of the nutrient layer, and serves as a highly precise ‘on/off’ switch for chemical reactions. We apply this design to trigger organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles synchronized with the motion of the microstructures and the driving external chemical stimulus. By exploiting a continuous feedback loop between various exothermic catalytic reactions in the nutrient layer and the mechanical action of the temperature-responsive gel, we then create exemplary autonomous, self-sustained homeostatic systems that maintain a user-defined parameter—temperature—in a narrow range. The experimental results are validated using computational modelling that qualitatively captures the essential features of the self-regulating behaviour and provides additional criteria for the optimization of the homeostatic function, subsequently confirmed experimentally. This design is highly customizable owing to the broad choice of chemistries, tunable mechanics and its physical simplicity, and may lead to a variety of applications in autonomous systems with chemo-mechano-chemical transduction at their core.

In this paper we show how animal personality could explain some of the large inter-individual variation in resting metabolic rate (MR) and explore methodological and functional linkages between personality and energetics. Personality will introduce variability in resting MR measures because individuals consistently differ in their stress response, exploration or activity levels, all of which influence MR measurements made with respirometry and the doubly-labelled water technique. Physiologists try to exclude these behavioural influences from resting MR measurements, but animal personality research indicates that these attempts are unlikely to be successful. For example, because reactive animals \"freeze\" when submitted to a stress, their MR could be classified as \"resting\" because of immobility when in fact they are highly stressed with an elevated MR. More importantly, recent research demonstrating that behavioural responses to novel and highly artificial stimuli are correlated with both behaviour and fitness under more natural circumstances calls into question the wisdom of excluding these behavioural influences on MR measurements. The reason that intra-specific variation in resting MR are so weakly correlated with daily energy expenditure (DEE) and fitness, may be that the latter two measures fully incorporate personality while the former partially excludes its influence. Because activity, exploration, boldness and aggressiveness are energetically costly, personality and metabolism should be correlated and physiological constraints may underlie behavioural syndromes. We show how physiological ecologists can better examine behavioural linkages between personality and metabolism, as required to better understand the physiological correlates of personality and the evolutionary consequences of metabolic variability.

Ingestion of agents that modify blood buffering action may affect high-intensity performance. Here we present a meta-analysis of the effects of acute ingestion of three such agents — sodium bicarbonate, sodium citrate and ammonium chloride — on performance and related physiological variables (blood bicarbonate, pH and lactate). A literature search yielded 59 useable studies with 188 observations of performance effects. To perform the mixed-model meta-analysis, all performance effects were converted into a percentage change in mean power and were weighted using standard errors derived from exact p-values, confidence limits (CLs) or estimated errors of measurement. The fixed effects in the meta-analytic model included the number of performance-test bouts (linear), test duration (log linear), blinding (yes/no), competitive status (athlete/nonathlete) and sex (male/female). Dose expressed as buffering mmoL/kg/body mass (BM) was included as a strictly proportional linear effect interacted with all effects except blinding. Probabilistic inferences were derived with reference to thresholds for small and moderate effects on performance of 0.5% and 1.5%, respectively. Publication bias was reduced by excluding study estimates with a standard error >2.7%. The remaining 38 studies and 137 estimates for sodium bicarbonate produced a possibly moderate performance enhancement of 1.7% (90% CL± 2.0%) with a typical dose of 3.5mmoL/kg/BM (~0.3 g/kg/BM) in a single 1-minute sprint, following blinded consumption by male athletes. In the 16 studies and 45 estimates for sodium citrate, a typical dose of 1.5mmoL/kg/BM (~0.5 g/kg/BM) had an unclear effect on performance of 0.0% (±1.3%), while the five studies and six estimates for ammonium chloride produced a possibly moderate impairment of 1.6% (±1.9%) with a typical dose of 5.5mmoL/kg/BM (~0.3 g/kg/BM). Study and subject characteristics had the following modifying small effects on the enhancement of performance with sodium bicarbonate: an increase of 0.5% (±0.6%) with a 1mmoL/kg/BM increase in dose; an increase of 0.6% (±0.4%) with five extra sprint bouts; a reduction of 0.6% (±0.9%) for each 10-fold increase in test duration (e.g. 1–10 minutes); reductions of 1.1%(±1.1%) with nonathletes and 0.7% (±1.4%) with females. Unexplained variation in effects between research settings was typically ±1.2%. The only noteworthy effects involving physiological variables were a small correlation between performance and pre-exercise increase in blood bicarbonate with sodium bicarbonate ingestion, and a very large correlation between the increase in blood bicarbonate and time between sodium citrate ingestion and exercise. The approximate equal and opposite effects of sodium bicarbonate and ammonium chloride are consistent with direct performance effects of pH, but sodium citrate appears to have some additional metabolic inhibitory effect. Important future research includes studies of sodium citrate ingestion several hours before exercise and quantification of gastrointestinal symptoms with sodium bicarbonate and citrate. Although individual responses may vary, we recommend ingestion of 0.3–0.5 g/kg/BM sodium bicarbonate to improve mean power by 1.7% (±2.0%) in high-intensity races of short duration.

The peptide hormone, hepcidin, is secreted from the liver in response to extracellular factors, including inflammation, and regulates iron homeostasis by controlling transmembrane iron transport. Vecchi et al. (p. 877 ) showed that intracellular stress signals in the endoplasmic reticulum also control hepcidin expression and can thus modulate local or systemic iron traffic. This mechanism occurs through the transcription factor CREBH, which is a known mediator of the inflammatory response. Collectively, the results suggest a direct link between the intracellular stress response, innate immunity, and iron metabolism. Stress signals in the endoplasmic reticulum activate a transcription factor that induces the expression of an iron-regulatory hormone. Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element–binding protein H), an ER stress–activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress–regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.