Ruth Gordillo

An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice

FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. In particular, the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lep(ob/ob) mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects.

Origin of Enantioselection in Hetero-Diels−Alder Reactions Catalyzed by Naphthyl-TADDOL

The asymmetric hetero-Diels-Alder reaction of benzaldehyde with 1-dimethylamino-3- tert-butyldimethylsiloxy butadiene catalyzed by ( R, R)-1-Np-TADDOL was studied using computational methods. A theoretical rationale was developed through the combined use of molecular mechanics and ONIOM(B3LYP/6-31G(d):AM1) calculations. The origins of stereoselection in this process were identified, and excellent correlation between experiment and theory was found.

Plasma ceramides are elevated in female children and adolescents with type 2 diabetes

Abstract Accumulation of ceramides within tissues induces insulin resistance. Moreover, adiponectin exerts its beneficial metabolic effects at least partially through ceramide catabolism. We hypothesized that specific plasma ceramide subspecies are elevated in obese children and adolescents with type 2 diabetes (T2D), and that they inversely correlate with adiponectin and measures of insulin sensitivity. This was a cross-sectional study. Participants included 14 obese female subjects with T2D, ages 10–17, and 14 lean healthy controls of the same age and gender. Fasting plasma ceramide subspecies were measured by quantitative tandem mass spectrometry. Subjects with T2D had higher concentrations of C22:0 and C20:0 ceramides, with a 2-fold increase in C18:0 ceramide and C24:1 dihydroceramide (p<0.05). C22:0, C20:0 and C18:0 ceramide correlated with decreased adiponectin concentrations, increased HOMA-IR, BMI Z-score, triglyceride and fasting blood glucose concentrations (p<0.05). Plasma levels of C18:0, C20:0 and C22:0 ceramide, as well as C24:1 dihydroceramide, were elevated in obese female children and adolescents with T2D. This may be a reflection of tissue insulin resistance and could be a result of low adiponectin levels.

Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation

Pathological expansion of adipose tissue contributes to the metabolic syndrome. Distinct depots develop at various times under different physiological conditions. The transcriptional cascade mediating adipogenesis is established in vitro, and centres around a core program involving PPARγ and C/EBPα. We developed an inducible, adipocyte-specific knockout system to probe the requirement of key adipogenic transcription factors at various stages of adipogenesis in vivo. C/EBPα is essential for all white adipogenic conditions in the adult stage, such as adipose tissue regeneration, adipogenesis in muscle and unhealthy expansion of white adipose tissue during high-fat feeding or due to leptin deficiency. Surprisingly, terminal embryonic adipogenesis is fully C/EBPα independent, but does however depend on PPARγ; cold-induced beige adipogenesis is also C/EBPα independent. Moreover, C/EBPα is not vital for adipocyte survival in the adult stage. We reveal a surprising diversity of transcriptional signals required at different stages of adipogenesis in vivo.

Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes β-cell regeneration

As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects. While many important functions have been attributed to adiponectin under high-fat diet conditions, little is known about its essential role under regular chow. Employing a mouse model with inducible, acute β-cell ablation, we uncovered an essential role of adiponectin under insulinopenic conditions to maintain minimal lipid homeostasis. When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue. In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality. In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin. Moreover, adiponectin is sufficient to mitigate local lipotoxicity in pancreatic islets, and it promotes reconstitution of β-cell mass, eventually reinstating glycemic control. We uncovered an essential new role for adiponectin, with major implications for type 1 diabetes. DOI: http://dx.doi.org/10.7554/eLife.03851.001

Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis

Objective Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. Methods Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Results Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. Conclusion These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids.

A role of the Inflammasome in the low storage capacity of the abdominal subcutaneous adipose tissue in obese adolescents

The innate immune cell sensor leucine-rich–containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome–related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.

An adipo-biliary-uridine axis that regulates energy homeostasis

Uridines rise and fall: Food for thought The nucleoside uridine is well known for its role in critical cellular functions such as nucleic acid synthesis. Its role in whole-animal physiology has received comparatively little attention. In mammals, plasma uridine levels are tightly regulated, but the underlying mechanisms are unclear. Studying mouse models, Deng et al. show that plasma uridine levels are controlled by feeding behavior (see the Perspective by Jastroch and Tschöp). Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease. Science, this issue p. aaf5375; see also p. 1124 Plasma uridine levels are controlled by feeding behavior, a discovery with possible implications for metabolic disease. INTRODUCTION Uridine is a pyrimidine nucleoside that is critical for cellular function and survival. In addition to its role in RNA and DNA biosynthesis, uridine is required for glycogen deposition, protein and lipid glycosylation, extracellular matrix biosynthesis, and detoxification of xenobiotics. Plasma uridine levels are maintained within a narrow range, and most cells depend on a readily available pool of uridine in plasma to maintain basic cellular functions. Enhanced understanding of the physiological mechanisms controlling biosynthesis and clearance of this metabolite has the potential to shed light on several disease states, including diabetes, cancer, and neurological disorders. RATIONALE Despite its pivotal physiological role, uridine has received limited attention in comparison to other nucleosides such as adenosine. Studying rodent models, we set out to define the mechanisms regulating plasma uridine levels and to dissect the molecular circuitry whereby uridine governs energy homeostasis in normal and obese conditions. RESULTS One of our key findings is that plasma uridine levels are subject to tight regulation during feeding and fasting in both rodents and humans. Plasma uridine levels are elevated during fasting and drop rapidly in the postprandial state. We demonstrate that liver is the predominant biosynthetic organ and contributor to plasma uridine in the fed state, whereas the adipocyte dominates uridine biosynthetic activity in the fasted state. Both glucose and uridine levels must be maintained in the fasted state, not only as basic building blocks for macromolecule biosynthesis, but also as fuels for metabolically active cell types such as neurons. We find that the fasting-induced rise in uridine is tightly linked to a drop in core body temperature driven by a reduction in metabolic rate. The fasting-induced drop in body temperature, although small, is highly reproducible and seen in both rodents and humans. Plasma uridine homeostasis thus links thermoregulation to the fasting/refeeding cycle. Leptin signaling governs uridine-dependent thermoregulation such that leptin deficiency amplifies fasting-induced declines in core temperature. Conversely, prolonged exposure to a high-fat diet blunts the fasting-induced body temperature drop. We clarify the mechanism underlying the rapid reduction of plasma uridine upon refeeding, which involves both reduction of uridine synthesis in adipocytes and enhancement of its clearance through the bile. Uridine from the digestive tract has a different fate than uridine derived biosynthetically from the adipocyte in the fasted state. Adipose tissue–derived uridine increases plasma uridine concentrations, which in turn elicit a hypothalamic response culminating in body temperature lowering. In contrast, gut-derived uridine is never fully released into the circulation, but rather is rapidly resorbed into bile again and effectively reused as part of an enterohepatic recycling process. This minimizes the effects of postprandial uridine absorption, obviating an impact on temperature control in the fed state. CONCLUSION Our results show that plasma uridine concentrations in mammals are regulated by fasting/refeeding. Adipocytes are key contributors to uridine supply during fasting, whereas biliary excretion is the primary mechanism for uridine clearance following food intake. Bile-mediated uridine release promotes body temperature declines during fasting and enhances insulin sensitivity in a leptin-dependent manner. Because nutrient intake triggers bile release, our work identifies a metabolic regulatory model in which feeding behavior directly regulates plasma uridine homeostasis, which then alters energy balance through thermoregulation. A regulatory model of energy homeostasis during fasting/refeeding. The liver is the predominant biosynthetic organ and contributor to plasma uridine in the fed state, whereas the adipocyte dominates uridine biosynthetic activity in the fasted state. Biliary excretion is the primary mechanism for plasma uridine clearance. Because nutrient intake triggers bile release, plasma uridine levels are elevated during fasting and drop rapidly in the postprandial state. The fasting-associated increase of plasma uridine elicits a hypothalamic response culminating in body temperature lowering, whereas bile-mediated uridine release promotes a decline of plasma uridine and enhances insulin sensitivity. Uridine, a pyrimidine nucleoside present at high levels in the plasma of rodents and humans, is critical for RNA synthesis, glycogen deposition, and many other essential cellular processes. It also contributes to systemic metabolism, but the underlying mechanisms remain unclear. We found that plasma uridine levels are regulated by fasting and refeeding in mice, rats, and humans. Fasting increases plasma uridine levels, and this increase relies largely on adipocytes. In contrast, refeeding reduces plasma uridine levels through biliary clearance. Elevation of plasma uridine is required for the drop in body temperature that occurs during fasting. Further, feeding-induced clearance of plasma uridine improves glucose metabolism. We also present findings that implicate leptin signaling in uridine homeostasis and consequent metabolic control and thermoregulation. Our results indicate that plasma uridine governs energy homeostasis and thermoregulation in a mechanism involving adipocyte-dependent uridine biosynthesis and leptin signaling.

Theoretical study of the molecular structure for zirconium complexes

Abstract This work constitutes a study guided to the design of the molecular geometry of ZrO 2 gels aided by computer-based calculations (Density-Functional Theory). The electronic and spectroscopic properties of two zirconium complexes, [Zr(OH) 6 ] 2− and [Zr(OH) 5 (OCH 2 CH 2 CH 3 )] 2− , are explored. Vibration frequencies and properties of nuclear magnetic resonance are theoretically studied.

Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate

In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen–challenged Ormdl3Δ2-3/Δ2-3/CC10 mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in Ormdl3Δ2-3/Δ2-3/CC10 and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3/CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3/CC10 mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.