Kegg Pathway: Fatty acid metabolism

Br J Pharmacol. 2008 May 12;
Sheng L, Qian Z, Shi Y, Yang L, Xi L, Zhao B, Xu X, Ji H

Background and purpose:The amelioration of insulin resistance by treatment with crocetin is closely related to the hypolipidaemic effect. The present study is designed to clarify the insulin-sensitizing mechanism of crocetin by elucidating the mechanism of regulation of lipid metabolism by crocetin.Experimental approach:Rats given a high-fat diet were treated with crocetin for 6 weeks before hyperinsulinaemic-euglycaemic clamp. (14)C-palmitate was used as tracer to track the fate of non-esterified Fatty acids or as substrate to measure beta-oxidation rate. Triglyceride clearance in plasma and lipoprotein lipase activity in tissues were tested. Content of lipids in plasma and tissues was determined. Real-time PCR was used to assay the level of mRNA from genes involved in non-esterified Fatty acid and triglyceride uptake and oxidation.Key results:Crocetin prevented high-fat-diet induced insulin resistance (increased clamp glucose infusion rate), raised hepatic non-esterified Fatty acid uptake and oxidation, accelerated triglyceride clearance in plasma, enhanced lipoprotein lipase activity in liver, and reduced the accumulation of detrimental lipids (DAG and long-chain acyl CoA) in liver and muscle. Genes involved in hepatic lipid metabolism which are regulated by peroxisome proliferator-activated receptor-alpha, were modulated to accelerate lipid uptake and oxidation.Conclusions and implications:Through regulating genes involved in lipid metabolism, crocetin accelerated hepatic uptake and oxidation of non-esterified Fatty acid and triglyceride, and reduced lipid availability to muscle, thus decreasing lipid accumulation in muscle and liver, and consequently improving sensitivity to insulin.British Journal of Pharmacology advance online publication, 12 May 2008; doi:10.1038/bjp.2008.160.

J Oleo Sci. 2008; 57(6): 335-43
Kanazawa T, Atsumi M, Mineo H, Fukushima M, Nishimura N, Noda T, Chiji H

Potato starch is known to have a higher concentration of phosphate than other starches. The presence of phosphate groups in amylopectin results in resistance to digestion by amylase. Therefore, there is a possibility that potato starch is slowly digested, inducing a physiological effect similar to that of resistant starch and indigestible oligosaccharides. The amount of phosphate group in starch differs with potato cultivar. In the present study, we investigated the effects of gelatinized potato starch containing a high level of phosphorus on lipid metabolism in rats. For this purpose, we determined lipid levels in the serum and liver in rats fed two kinds of gelatinized potato starches with different phosphorus contents. Four groups of male Sprague-Dawley rats were fed a 60% sucrose diet (control) or one of three diets containing cornstarch (CS), Benimaru (BM) potato starch or Hokkaikogane (HK) potato starch. Fat pad weight was slightly decreased in the HK diet group compared with that in the other groups. Free Fatty acids in serum were significantly lowered by dietary HK starch compared with control, and serum triglyceride in rats fed the HK diet was also decreased. In the BM and HK diet groups, triglyceride levels in the liver were decreased compared with that in the control and CS groups. As for hepatic total cholesterol level, there were no significant differences among three starch diet groups. Fecal bile acid excretion was greater in the two potato starch groups than in the control group. On the other hand, there were no significant differences in cecal short-chain Fatty acid content or pH. Thus, we conclude that dietary gelatinized potato starch reduces free Fatty acid and triglyceride in serum and hepatic triglyceride, but does not affect cecal fermentation.

Am J Physiol Heart Circ Physiol. 2008 May 9;
Tominaga H, Katoh H, Odagiri K, Takeuchi Y, Kawashima H, Saotome M, Urushida T, Satoh H, Hayashi H

Although mitochondrial oxidative catabolism of Fatty acid (FA) is a major energy source for the adult mammalian heart, cardiac lipotoxity resulting from elevated serum FA and enhanced FA use has been implicated in the pathogenesis of heart failure. To investigate the effects of the intermediates of FA metabolism, palmitoyl-L-carnitine (Pal-car) and palmitoyl-CoA (Pal-CoA), on mitochondrial function, we measured membrane potential (DeltaPsim), opening of the mitochondrial permeability transition pore (mPTP) and the production of reactive oxygen species (ROS) in saponin-treated rat ventricular myocytes with a laser scanning confocal microscope. Our results revealed that: 1) lower concentrations of Pal-car (1 and 5 microM) caused a slight hyperpolarization of DeltaPsim (TMRE intensity increased to 115.5 +/- 5.4 % and 110.7 +/- 1.6 % of the baseline, respectively. p<0.05) but did not open mPTP, 2) a higher concentration of Pal-car (10 microM) depolarized DeltaPsim (TMRE intensity decreased to 61.9 +/- 12.2 % of the baseline, p<0.01) and opened mPTP (calcein intensity decreased to 70.7 +/- 2.8 % of the baseline, p<0.01), 3) Pal-CoA depolarized DeltaPsim without opening mPTP, and 4) only the higher concentration of Pal-car (10 microM) increased ROS generation (DCF intensity increased to 3.4 +/- 0.3 fold of the baseline). We concluded that excessive exogenous intermediates of long chain saturated FA may disturb mitochondrial function in different ways between Pal-car and Pal-CoA. The distinct mechanisms of the deteriorating effects of long chain FA on mitochondrial function are important for our understanding of the development of cardiac diseases in systemic metabolic disorders. Key words: Palmitoyl-L-carnitine and Palmitoyl CoA, mitochondrial membrane potential, mitochondrial permeability transition pore, ROS production.

Cardiovasc Res. 2008 May 9;
Schwenk RW, Luiken JJ, Bonen A, Glatz JF

Circulating long chain Fatty acids (LCFA) and glucose are the main sources for energy production in the heart. In the healthy heart the ratio of glucose and LCFA oxidation is sensitively balanced and chronic alterations in this substrate mix are closely associated to cardiac dysfunction. While it has been accepted for several years that cardiac glucose uptake is mediated by facilitated transport, i.e., by means of the glucose transport proteins GLUT1 and GLUT4, only in the last few years it has become clear that proteins with high-affinity binding sites to LCFA, referred to as LCFA transporters, are responsible for bulk LCFA uptake. Similar to the GLUTs, the LCFA transporters CD36 and FABP(pm) can be recruited from an intracellular storage compartment to the sarcolemma to increase the rate of substrate uptake. Permanent relocation of LCFA transporters, mainly CD36, from intracellular stores to the sarcolemma is accompanied by accumulation of lipids and lipid metabolites in the heart. As a consequence, insulin-signalling and glucose utilization are impaired, leading to decreased contractile activity of the heart. These observations underline the particular role and interplay of substrate carriers for glucose and LCFA in modulating cardiac metabolism, and the development of heart failure. The signalling and trafficking pathways and subcellular machinery regulating translocation of glucose and LCFA transporters are beginning to be unravelled. More knowledge on substrate transporter recycling, especially the similarities and differences between glucose and LCFA transporters, is expected to enable novel therapies aimed at changing the distribution of glucose and LCFA transporters, thereby manipulating the substrate preference of the diseased heart to help restore cardiac function.

Toxicol Pathol. 2008 May 8;
Rosen MB, Abbott BD, Wolf DC, Corton JC, Wood CR, Schmid JE, Das KP, Zehr RD, Blair ET, Lau C

Health concerns have been raised because perfluorooctanoic acid (PFOA) is commonly found in the environment and can be detected in humans. In rodents, PFOA is a carcinogen and a developmental toxicant. PFOA is a peroxisome proliferator-activated receptor alpha(PPARalpha) activator; however, PFOA is capable of inducing heptomegaly in the PPARalpha-null mouse. To study the mechanism associated with PFOA toxicity, wild-type and PPARalpha-null mice were orally dosed for 7 days with PFOA (1 or 3 mg/kg) or the PPARalphaagonist Wy14,643 (50 mg/kg). Gene expression was evaluated using commercial microarrays. In wild-type mice, PFOA and Wy14,643 induced changes consistent with activation of PPARalpha. PFOA-treated wild-type mice deviated from Wy14,643-exposed mice with respect to genes involved in xenobiotic metabolism. In PFOA-treated null mice, changes were observed in transcripts related to Fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle regulation. Hence, a component of the PFOA response was found to be independent of PPARalpha. Although the signaling pathways responsible for these effects are not readily apparent, overlapping gene regulation by additional PPAR isoforms could account for changes related to Fatty acid metabolism and inflammation, whereas regulation of xenobiotic metabolizing genes is suggestive of constitutive androstane receptor activation.

Prostaglandins Leukot Essent Fatty acids. 2008 May 6;
Talib LL, Yassuda MS, O Diniz BS, Forlenza OV, Gattaz WF

Phospholipases A(2) (PLA(2)) are ubiquitous enzymes involved in membrane Fatty acid metabolism and intracellular signalling. Recent studies have shown that PLA(2) subtypes are implicated in the modulation of pathways related to memory acquisition and retrieval. We investigated the effects of cognitive training on platelet PLA(2) activity in healthy elderly individuals. Twenty-three cognitively unimpaired older adults were randomly assigned to receive memory training or standard outpatient care only. Both groups were cognitively assessed by the same protocol, and the experimental group (EG) underwent a four-session memory training intervention. Pre- and post-test measures included prose and list recall, WAIS-III digit symbol, strategy use measures and platelet PLA(2) group activity. After cognitive training, patients in the EG group had significant increase in cytosolic, calcium-dependent PLA(2) (cPLA(2)), extracellular (or secreted), calcium-dependent PLA(2) (sPLA(2)), total platelet PLA(2) activity, and significant decrease in platelet calcium-independent PLA(2) (iPLA(2)) activity. Our results suggest that memory training may have a modulating effect in PLA(2)-mediated biological systems associated with cognitive functions and neurodegenerative diseases.

IDrugs. 1998 Nov; 1(7): 752-3
Schloss JV

This symposium was organized by Dan Flynn (Monsanto Life Sciences, USA) and Timothy M Willson (Glaxo Wellcome, USA). PPARs (peroxisome proliferator-activated receptors), are nuclear hormone receptors that govern glucose and lipid homeostasis. There are several subtypes of receptors that share activation by unsaturated Fatty acids and work in combination with retinoic acid receptors (RXR), which were a topic covered in an earlier symposium. Two classes of chemistry were discussed at the symposium: (i) thiazolidinediones, that interact directly with PPARs and alter lipid metabolism; and, (ii) benzothiepines or benzothiazepines, that inhibit the ileal bile acid transporter (IBAT) and reduce cholesterol levels by increasing bile acid excretion.

Int J Biol Sci. 2008; 4(2): 96-102
Jiang Z, Michal JJ, Tobey DJ, Wang Z, Macneil MD, Magnuson NS

Several reports have shown that urotensin 2 (UTS2) and its receptor (UTS2R) are involved in glucose metabolism and insulin resistance, which lead to development of type 2 diabetes mellitus (T2DM) in humans. In the present study, we annotated both bovine UTS2 and UTS2R genes and identified 5 single nucleotide polymorphisms (SNPs) for the former gene and 14 mutations for the latter gene. Four mutations were genotyped on a Wagyu x Limousin reference population, including 6 F(1 )bulls, 113 F(1 )dams and ~250 F(2 )progeny. Among 12 phenotypes related to fat deposition and Fatty acid composition, we observed that the UTS2 gene was significantly associated with the amount of skeletal saturated Fatty acids, while its receptor (UTS2R) gene had significant effects on amounts of saturated and monounsaturated Fatty acids, Delta(9) desaturase activity for converting 16:0 into 16:1, muscle fat (marbling) score and Longissimus Dorsi muscle area. However, in this population, these markers were not associated with subcutaneous fat depth or percent kidney, pelvic and heart fat. We also found that mutations in the promoter regions altered the promoter activities in both genes and coding SNPs might affect the mRNA stability in the UTS2R gene. Overall, our present study provides the first evidence that both UTS2 and UTS2R genes regulate skeletal muscle fat accumulation and Fatty acid metabolism, thus indicating their potential pathological functions related to obesity and T2DM in humans.

J Mol Cell Cardiol. 2008 Apr 4;
Madrazo JA, Kelly DP

Common causes of heart failure are associated with derangements in myocardial fuel utilization. Evidence is emerging that metabolic abnormalities may contribute to the development and progression of myocardial disease. The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors has been shown to regulate cardiac fuel metabolism at the gene expression level. The three PPAR family members (alpha, beta/delta and gamma) are uniquely suited to serve as transducers of developmental, physiological, and dietary cues that influence cardiac Fatty acid and glucose metabolism. This review describes murine PPAR loss- and gain-of-function models that have shed light on the roles of these receptors in regulating myocardial metabolic pathways and have defined key links to disease states including the hypertensive and diabetic heart.

J Neuroendocrinol. 2008 May; 20 Suppl 1: 94-9
Hansen HS, Artmann A

The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids derived from the n-6 family of polyunsaturated Fatty acids that are essential Fatty acids. Symptoms of essential Fatty acid deficiency in rats - growth retardation, scaly skin, and increased transepidermal water loss - can mainly be attributed to lack of linoleic acid as a structural element of the epidermis. Arachidonic acid, however, also serve essential functions, particularly in cellular signalling via its precursor role for numerous oxygenated derivatives such as prostaglandins, leukotrienes, hepoxilins and other eicosanoids. Furthermore, arachidonic acid is also a structural part of endocannabinoids that have signalling functions in relation to modulation of neurotransmitter release, which might involve physiological and pathophysiological phenomena such as regulation of appetite, energy metabolism, pain perception, memory and learning. Furthermore, along with AEA formation other acylethanolamides are always formed - e.g., oleoylethanolamide (OEA), that can inhibit food intake, and palmitoylethanolamide, that is anti-inflammatory - possibly through activation of peroxisome proliferator activated receptor alpha (PPAR alpha) and/or GPR119. As all these unsaturated Fatty acids are ingested daily in smaller or larger amounts, one can ask whether different dietary fats can affect the levels of these Fatty acids in the tissues and thereby the quantitative formation of these bioactive signalling molecules. Generally, in vivo arachidonic-acid-derived eicosanoid production can be increased and decreased by prolonged feeding with pharmacological levels of arachidonic acid and long-chain (n-3) Fatty acids (fish oil), respectively. Changes in levels of these two Fatty acids within the traditional human diet hardly affects the eicosanoid production, however. Moreover, preliminary data suggest that dietary intake of arachidonic acid and fish oil also doesn't easily affect endocannabinoid formation; however, dietary fat in terms of saturated, polyunsaturated and monounsaturated seems to affect tissue levels of AEA, 2-AG and OEA.

Appl Physiol Nutr Metab. 2008 Jun; 33(3): 441-9
Tokmakidis SP, Karamanolis IA

This study examined the effects of pre-exercise carbohydrate ingestion on exercise metabolism and endurance running capacity. Eleven active subjects (VO2 max 49.0 +/- 1.7 mL.kg-1.min-1, mean +/- SE) performed two exercise trials 15 min after ingesting glucose (G; 1 g.kg body mass-1) and placebo (CON). Each subject ran on a level treadmill for 5 min at 60%, 45 min at 70%, and then at 80% of VO2 max until exhaustion. Serum glucose and plasma insulin reached their peak concentrations (p < 0.01) 15 min after glucose ingestion and declined at the onset of exercise. Serum glycerol concentrations were lower (p < 0.01) in the G trial than in the CON trial after 30 min of exercise to exhaustion. In addition, after 45 min of exercise to exhaustion, the levels of free Fatty acids were lower in G than in CON (p < 0.05). No differences were observed in carbohydrate oxidation rates during exercise between treatments (G, 2.53 +/- 0.08 g.min-1; CON, 2.40 +/- 0.09 g.min-1). Time to exhaustion was 12.8% longer in G (p < 0.01) than in CON. These results suggest that glucose ingestion 15 min before prolonged exercise provides an additional carbohydrate source to the exercising muscle, thus improving endurance running capacity.

Curr Opin Lipidol. 2008 Jun; 19(3): 277-84
Hussain MM, Rava P, Pan X, Dai K, Dougan SK, Iqbal J, Lazare F, Khatun I

PURPOSE OF REVIEW: This review summarizes recent advances about the role of microsomal triglyceride transfer protein in plasma and tissue lipid homeostasis. RECENT FINDINGS: Microsomal triglyceride transfer protein emerged as a phospholipid transfer protein and acquired triacylglycerol transfer activity during evolution from invertebrates to vertebrates. These activities are proposed to participate in 'nucleation' and 'desorption' steps during the biosynthesis of primordial apoB-containing lipoproteins. Microsomal triglyceride transfer protein also transfers phospholipids to the glycolipid antigen presentation molecule CD1d. Under physiologic conditions, plasma apoB-containing lipoproteins and microsomal triglyceride transfer protein expression exhibit diurnal variations synchronized by food and light. Microsomal triglyceride transfer protein is regulated at the transcriptional level. HNF4alpha is critical for its transcription. Other transcription factors along with coactivators and corepressors modulate microsomal triglyceride transfer protein expression. Reductions in microsomal triglyceride transfer protein mRNA and activity are related to steatosis in HCV-3 infected patients. CCl4 induces steatosis by enhancing proteasomal degradation of microsomal triglyceride transfer protein and can be partially avoided by inhibiting this degradation. Chemical antagonists cause hepatosteatosis, but this was not seen in the absence of Fatty acid binding protein. SUMMARY: Microsomal triglyceride transfer protein is a target to lower plasma lipids and to reduce inflammation in certain immune disorders. More knowledge is required, however, regarding its regulation and its role in the biosynthesis of apoB-containing lipoproteins and CD1d.

Curr Opin Lipidol. 2008 Jun; 19(3): 248-56
Flowers MT, Ntambi JM

PURPOSE OF REVIEW: Stearoyl-coenzyme A desaturase 1 is a delta-9 Fatty acid desaturase that catalyzes the synthesis of monounsaturated Fatty acids and has emerged as a key regulator of metabolism. This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease. RECENT FINDINGS: Scd1-deficient mice have reduced lipid synthesis and enhanced lipid oxidation, thermogenesis and insulin sensitivity in various tissues including liver, muscle and adipose tissue due to transcriptional and posttranscriptional effects. These metabolic changes protect Scd1-deficient mice from a variety of dietary, pharmacological and genetic conditions that promote obesity, insulin resistance and hepatic steatosis. Stearoyl-coenzyme A desaturase 1 is required to guard against dietary unsaturated fat deficiency, leptin deficiency-induced diabetes, and palmitate-induced lipotoxic insults in muscle and pancreatic beta-cells. Paradoxical observations of increased muscle stearoyl-coenzyme A desaturase 1 during obesity, starvation and exercise raise questions as to the role of stearoyl-coenzyme A desaturase 1 in this tissue. Mice with a liver-specific loss of stearoyl-coenzyme A desaturase 1, and inhibition of stearoyl-coenzyme A desaturase 1 via antisense or RNA interference, recapitulate only a subset of the phenotypes observed in global Scd1 deficiency, indicating the involvement of multiple tissues. SUMMARY: Recent studies in humans and animal models have highlighted that modulation of stearoyl-coenzyme A desaturase 1 activity by dietary intervention or genetic manipulation strongly influences several facets of energy metabolism to affect susceptibility to obesity, insulin resistance, diabetes and hyperlipidemia.

Curr Opin Lipidol. 2008 Jun; 19(3): 242-7
Jump DB

PURPOSE OF REVIEW: The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, Fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated Fatty acid regulation of hepatic gene transcription. RECENT FINDINGS: Dietary n-3 polyunsaturated Fatty acid regulates hepatic gene expression by targeting three major transcriptional regulatory networks: peroxisome proliferator-activated receptor alpha, sterol regulatory element binding protein-1 and the carbohydrate regulatory element binding protein/Max-like factor X heterodimer. 22: 6,n-3, the most prominent n-3 polyunsaturated Fatty acid in tissues, is a weak activator of peroxisome proliferator-activated receptor alpha. Hepatic metabolism of 22: 6,n-3, however, generates 20: 5,n-3, a strong peroxisome proliferator-activated receptor alpha activator. In contrast to peroxisome proliferator-activated receptor alpha, 22: 6,n-3 is the most potent Fatty acid regulator of hepatic sterol regulatory element binding protein-1. 22: 6,n-3 suppresses sterol regulatory element binding protein-1 gene expression while enhancing degradation of nuclear sterol regulatory element binding protein-1 through 26S proteasome and Erk1/2-dependent mechanisms. Both n-3 and n-6 polyunsaturated Fatty acid suppress carbohydrate regulatory element binding protein and Max-like factor X nuclear abundance and interfere with glucose-regulated hepatic metabolism. SUMMARY: These studies have revealed unique mechanisms by which specific polyunsaturated Fatty acids control peroxisome proliferator activated receptor alpha, sterol regulatory element binding protein-1 and carbohydrate regulatory element binding protein/Max-like factor X function. As such, specific metabolic and signal transduction pathways contribute significantly to the Fatty acid regulation of these transcription factors and their corresponding regulatory networks.

Curr Opin Lipidol. 2008 Jun; 19(3): 221-8
Adeli K, Lewis GF

PURPOSE OF REVIEW: Excessive postprandial lipemia is highly prevalent in obese and insulin-resistant/type 2 diabetic individuals and substantially increases the risk of atherosclerosis and cardiovascular disease. This article will review our current understanding of the link between insulin resistance and intestinal lipoprotein overproduction and highlight some of the key recent findings in the field. RECENT FINDINGS: Emerging evidence from several animal models of insulin resistance as well as insulin-resistant humans clearly supports the link between insulin resistance and aberrant intestinal lipoprotein metabolism. In insulin-resistant states, elevated free Fatty acid flux into the intestine, downregulation of intestinal insulin signaling and upregulation of microsomal triglyceride transfer protein all appear to stimulate intestinal lipoprotein production. Gut peptides, GLP-1 and GLP-2, may be important regulators of intestinal lipid absorption and lipoprotein production. SUMMARY: Available evidence in humans and animal models strongly favors the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of triglyceride-rich lipoproteins. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors all contribute to the enhanced formation and secretion of triglyceride-rich lipoproteins.

J Am Coll Nutr. 2008 Feb; 27(1): 109-16
Robert L, Narcy A, Rayssiguier Y, Mazur A, Rémésy C

OBJECTIVE: Consumption of high levels of simple carbohydrates is associated with several metabolic disorders in humans and in laboratory animals, including symptoms of an early stage of metabolic syndrome (syndrome X). This disorder has several cardiovascular risk factors, such as hypertriglyceridemia, and is associated with an increase in oxidative stress. In contrast to sucrose, potato, a source of complex carbohydrates and antioxidant micronutrients, was thought to improve lipid metabolism and antioxidant protection. METHODS: We investigated the effects of diets containing i) complex dietary carbohydrates and antioxidant micronutrients (potato Solanum tuberosum L.), ii) complex carbohydrates (starch) and iii) a simple carbohydrate (sucrose) on lipid metabolism and antioxidant status in rats. RESULTS: An increase in short chain Fatty acid (SCFA) pools was observed in the cecum of rats fed a potato-based diet, resulting from an increase in all SCFAs, especially propionate (+360%, P < 0.0001). Feeding rats a potato-based diet for 3 weeks led to a decrease in cholesterol (-37%, potato vs. control and -32%, potato vs. sucrose) and triglycerides (-31%, potato vs. control and -43%, potato vs. sucrose) concentrations in triglyceride-rich lipoproteins (TGRLP) fractions. The antioxidant status was decreased by sucrose consumption and improved by potato consumption. CONCLUSIONS: Our present results suggest that consumption of complex carbohydrates (provided as cooked potatoes), in combination with different antioxidant micronutrients, may enhance the antioxidant defences and improve lipid metabolism, when compared with starch (complex carbohydrates) and to sucrose consumption (source of simple sugar). These effects limit oxidative stress and reduce the risk of developing the associated degenerative diseases, including cardiovascular disease, and could have potential in cardiovascular disease prevention.

Cell Metab. 2008 May 7; 7(5): 389-399
López M, Lage R, Saha AK, Pérez-Tilve D, Vázquez MJ, Varela L, Sangiao-Alvarellos S, Tovar S, Raghay K, Rodríguez-Cuenca S, Deoliveira RM, Castañeda T, Datta R, Dong JZ, Culler M, Sleeman MW, Alvarez CV, Gallego R, Lelliott CJ, Carling D, Tschöp MH, Diéguez C, Vidal-Puig A

Current evidence suggests that hypothalamic Fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of Fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates Fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin's effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic Fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.

Hepatology. 2008 May 5;
Herrema H, Derks TG, van Dijk TH, Bloks VW, Gerding A, Havinga R, Tietge UJ, Müller M, Smit GP, Kuipers F, Reijngoud DJ

Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial Fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD(-/-) mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD(-/-) mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) and decreased peroxisome proliferator-activated receptor alpha (Ppar alpha) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD(-/-) mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD(-/-) mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD(-/-) mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD(-/-) mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD(-/-) mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD(-/-) mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial Fatty acid oxidation. (HEPATOLOGY 2008.).

BMC Med Genomics. 2008 May 6; 1(1): 14
de Wit NJ, Bosch-Vermeulen H, de Groot PJ, Hooiveld GJ, Grootte Bromhaar MM, Jansen J, Muller M, van der Meer R

ABSTRACT: BACKGROUND: Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice. METHODS: Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the Fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays. RESULTS: The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance. CONCLUSIONS: During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.

Mol Biochem Parasitol. 2008 Mar 21;
Portal P, Villamil SF, Alonso GD, De Vas MG, Flawiá MM, Torres HN, Paveto C

Cytochrome P450 hemoproteins (CYPs) are involved in the synthesis of endogenous compounds such as steroids, Fatty acids and prostaglandins as well as in the activation and detoxification of foreign compounds including therapeutic drugs. Cytochrome P450 reductase (CPR, E.C.1.6.2.4) transfers electrons from NADPH to a number of hemoproteins such as CYPs, cytochrome c, cytochrome b5, and heme oxygenase. This work presents the complete sequences of three non-allelic CPR genes from Trypanosoma cruzi. The encoded proteins named TcCPR-A, TcCPR-B and TcCPR-C have calculated molecular masses of 68.6kDa, 78.4kDa and 71.3kDa, respectively. Deduced amino acid sequences share 11% amino acid identity, possess the conserved binding domains for FMN, FAD and NADPH and differ in the hydrophobic 27-amino acid residues of the N-terminal extension, which is absent in TcCPR-A. Every T. cruzi CPRs, TcCPR-A, TcCPR-B and TcCPR-C, were cloned and expressed in Escherichia coli. All of the recombinant enzymes reduced cytochrome c in a NADPH absolutely dependent manner with low K(m) values for this cofactor. They all were also strongly inhibited by diphenyleneiodonium, a classical flavoenzyme inhibitor. In addition, TcCPRs could support CYP activities when assayed in reconstituted systems containing rat liver microsomes. Polyclonal antiserum rose against the recombinant enzymes TcCPR-A and TcCPR-B demonstrated its presence in every T. cruzi developmental stages, with a remarkable expression of TcCPR-A in cell-cultured trypomastigotes. Overexpression of TcCPR-B in T. cruzi epimastigotes increased its resistance to the typical chemotherapeutic agents Nifurtimox and Benznidazole. We suggest a participation of TcCPR-B in the detoxification metabolism of the parasite.