Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the postgenomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports the first systems biology integration of metabolomics, transcriptomics, and proteomics data to characterize essential metabolic pathways involved in the tick response to A. phagocytophilum infection. The ISE6 tick cells used in this study constitute a model for hemocytes involved in pathogen infection and immune response. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. Additionally, ticks benefit from A. phagocytophilum infection by increasing survival while pathogens guarantee transmission. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cell's ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify cell pathways and molecular mechanisms involved in tick-pathogen interactions. Data are available via ProteomeXchange with identifier PXD002181. Molecular & Cellular

The effect of thyroid hormones on metabolism has long supported their potential as drugs to stimulate fat reduction, but the concomitant induction of a thyrotoxic state has greatly limited their use. Recent evidence suggests that 3,5-diiodo-L-thyronine (T2), a naturally occurring iodothyronine, stimulates metabolic rate via mechanisms involving the mitochondrial apparatus. We examined whether this effect would result in reduced energy storage. Here, we show that T2 administration to rats receiving a high-fat diet (HFD) reduces both adiposity and body weight gain without inducing thyrotoxicity. Rats receiving HFD + T2 showed (when compared with rats receiving HFD alone) a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, appoximately 50% less fat mass, a complete disappearance of fat from the liver, and significant reductions in the serum triglyceride and cholesterol levels (-52% and -18%, respectively). Thyroid hormones and thyroid-stimulating hormone (TSH) serum levels were not influenced by T2 administration. The biochemical mechanism underlying the effects of T2 on liver metabolism involves the carnitine palmitoyl-transferase system and mitochondrial uncoupling. If the results hold true for humans, pharmacological administration of T2 might serve to counteract the problems associated with overweight, such as accumulation of lipids in liver and serum, without inducing thyrotoxicity. However, the results reported here do not exclude deleterious effects of T2 on a longer time scale as well as do not show that T2 acts in the same way in humans.

OBJECTIVEHigh-fat diets (HFDs) are known to induce insulin resistance. Previously, we showed that 3,5-diiodothyronine (T2), concomitantly administered to rats on a 4-week HFD, prevented gain in body weight and adipose mass. Here we investigated whether and how T2 prevented HFD-induced insulin resistance.RESEARCH DESIGN AND METHODSWe investigated the biochemical targets of T2 related to lipid and glucose homeostasis over time using various techniques, including genomic and proteomic profiling, immunoblotting, transient transfection, and enzyme activity analysis.RESULTSHere we show that, in rats, HFD feeding induced insulin resistance (as expected), whereas T2 administration prevented its onset. T2 did so by rapidly stimulating hepatic fatty acid oxidation, decreasing hepatic triglyceride levels, and improving the serum lipid profile, while at the same time sparing skeletal muscle from fat accumulation. At the mechanistic level, 1) transfection studies show that T2 does not act via thyroid hormone receptor β; 2) AMP-activated protein kinase is not involved in triggering the effects of T2; 3) in HFD rats, T2 rapidly increases hepatic nuclear sirtuin 1 (SIRT1) activity; 4) in an in vitro assay, T2 directly activates SIRT1; and 5) the SIRT1 targets peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC-1α) and sterol regulatory element–binding protein (SREBP)-1c are deacetylated with concomitant upregulation of genes involved in mitochondrial biogenesis and downregulation of lipogenic genes, and PPARα/δ-induced genes are upregulated, whereas genes involved in hepatic gluconeogenesis are downregulated. Proteomic analysis of the hepatic protein profile supported these changes.CONCLUSIONST2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and, finally, prevention of diet-induced insulin resistance.

The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones (THs) in almost all tissues. Particular attention has been devoted by scientists to the effects of THs on lipid metabolism. Among others, effects related to cholesterol, lipid handling, and cardiac performance have been the subject of study. Many reports are present in the literature concerning the calorigenic effect of THs, with most of them aimed at identifying the molecular basis of this effect. However, at the moment the mechanism(s) underlying the metabolic effects of THs remain to be elucidated. THs exert most of their effects though TH receptors (TRs). However, some effects of THs cannot be explained by a nuclear-mediated pathway, and recently an increasing number of nonnuclear actions have been described, which can provide a regulatory system of which the effects differ from those mediated on the transcriptional level by TRs. Some of the TH derivatives (naturally occurring metabolites and analogs) possess biological activities. TH-related biological effects have been described for physiological products such as tetraiodothyroacetic acid (Tetrac) and triiodothyroacetic acid (Triac) (via oxidative deamination and decarboxylation of thyroxine [T4] and triiodothyronine [T3] alanine chain), 3,3',5'-triiodothyronine (rT3) (via T4 and T3 deiodination), 3,3'-diiodothyronine (3,3'-T2) and 3,5-diiodothyronine (T2) (via T4, T3, and rT3 deiodination), and 3-iodothyronamine (T1AM) and thyronamine (T0AM) (via T4 and T3 deiodination and amino acid decarboxylation), as well as for TH structural analogs, such as 3,5,3'-triiodothyropropionic acid (Triprop), 3,5-dibromo-3-pyridazinone-l-thyronine (L-940901), N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid (CGS 23425), 3,5-dimethyl-4[(4'-hydroxy-3'-isopropylbenzyl)-phenoxy] acetic acid (GC-1), 3,5-dichloro-4[(4-hydroxy-3-isopropylphenoxy)phenyl] acetic acid (KB-141), and 3,5-diiodothyropropionic acid (DITPA). Most of these compounds have interesting properties: counteracting lipid accumulation, reducing cholesterol level, and increasing lipid metabolism without cardiotoxic effects. Hopefully, further studies on basic mechanisms of such compounds will be harbingers of more knowledge on the metabolic effects of TH derivatives and on their possible clinical application.

Thyroid hormones exert profound effects on the energy metabolism. An inspection of the early and more recent literature shows that several targets at the cellular level have been identified. Since their effects on the nuclear signalling pathway have already been well-defined and extensively reviewed, this article focuses on the regulation of mitochondrial activity by thyroid hormones. Mitochondria, by virtue of their biochemical functions, are a natural candidate as a direct target for the calorigenic effects of thyroid hormones. To judge from results coming from various laboratories, it is quite conceivable that mitochondrial activities are regulated both directly and indirectly. Not only triiodo-L-thyronine, but also diiodothyronines are active in regulating the energy metabolism. They influence the resting metabolism in rats with 3,5-diiodo-Lthyronine seeming to show a clearer effect.z 1999 Federation of European Biochemical Societies.

Among the most pronounced physiological effects attributed to thyroid hormones in many adult endothermic vertebrates is their control over metabolism. Although the first evidence of an increase in metabolic rate in subjects given thyroid extract was reported as long ago as 1895 by Magnus-Levy, the literature contains very few papers dealing with the action of thyroxine (TÚ) and T× on metabolic rate of whole animals. Furthermore, although more than 30 years have elapsed since the appearance of the articles by Tata (Tata, Ernster & Lindberg, 1962;Tata, 1963) on the control of basal metabolic rate by thyroid hormones, the mechanism by which thyroid hormones influence basal or resting metabolic rate in whole animals (also called the calorigenic effect) is very poorly understood. Several hypotheses have been proposed to explain the calorigenic effect of thyroid hormones, but none has received universal acceptance (Sestoft, 1980). Indeed, conflicting results are to be found in the literature and a debate is still in progress as to whether the cellular target for the early action of thyroid hormones on energy metabolism is the nucleus or the mitochondria (for review, see Soboll, 1993). To some extent, the controversies may be a consequence of the use of a wide variety of animal models in the various Journal of Physiology (1997) ) either with one of the Tµs or with T×. Injection of T× induced an increase of about 35% in RM that started 25-30 h after the injection and lasted until 5-6 days after the injection, the maximal value being observed at 50-75 h. The injection of Tµs evoked a temporally different pattern of response. The increases in RM started 6-12 h after the injection, had almost disappeared after 48 h, and the maximal stimulation was observed at 28-30 h. 3. When actinomycin D (an inhibitor of protein synthesis) and T× were given together, the stimulation of RM was almost completely abolished. The simultaneous injection of actinomycin D and either of the Tµs, on the other hand, did not cause any attenuation of the stimulation seen with the Tµs alone. 4. Following chronic treatment (3 weeks) with either T× or Tµs there was a stimulation of organ growth only after the administration of T×. 5. Chronic administration of either Tµs or T× to hypothyroid rats significantly enhanced the oxidative capacity of each of the tissues considered. In the case of Tµs the stimulation was almost the same whether it was expressed as an increase in specific activity or total tissue activity. In the case of T× the increases were, in the main, secondary to the hypertrophic or hyperplastic effect. 6. These results indicate that Tµs and T× exert different effects on RM. The effects of Tµs are rapid and possibly mediated by their direct interaction with mitochondria. Those of T× are slower and more prolonged, and at least partly attributable to a modulation of the cellularity of tissues that are metabolically very active.

Fibrates are hypolipidemic drugs that activate the peroxisome proliferator-activated receptors. Since fibrates may also increase energy expenditure, we investigated whether fenofibrate (FF) had this effect in diet-induced obese rats. A 2-month administration of a high-fat palatable diet to adult rats increased body weight by 25% and white adipose mass by 163% compared with a standard diet. These effects were prevented by FF, both when administered for the 2 months of high-fat feeding and when given for only the second month. Consequently, FFtreated rats had a final body weight and white adipose tissue mass similar to untreated animals on the standard diet. FF also increased resting metabolic rate, hepatic peroxisomal and mitochondrial palmitoyl-dependent oxygen uptake and mRNA levels of acyl-CoA oxidase and lipoprotein lipase. Finally, FF lowered mRNA levels of uncoupling protein-2 and did not affect mitochondrial respiration in skeletal muscle. Therefore, FF seems to act as a weight-stabilizer mainly through its effect on liver metabolism. ß 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

No abstract