Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men

CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. OBJECTIVE: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. DESIGN AND SETTING: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. PATIENTS AND PARTICIPANTS: Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. CONCLUSIONS: Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.     

C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients

This study aimed to assess the role of complement C3, hormone-sensitive lipase (HSL), and peroxisome proliferator-activated receptor gamma (PPARgamma) gene expression in familial combined hyperlipidemia (FCHL). mRNA expression of these 3 determinants of adipose tissue fatty acid (FA) metabolism was quantified in subcutaneous adipose tissue of 41 Finnish FCHL patients and 14 normolipidemic control subjects. No difference in steady-state mRNA expression level of C3, HSL, or PPARgamma mRNA was detected between the FCHL patients and the control subjects. Adipose tissue C3 mRNA expression level correlated with the area under the curve (AUC) for glucose and for insulin in FCHL patients and control subjects. HSL mRNA level was positively correlated with waist-to-hip ratio in patients, whereas the correlation was negative in control subjects. A significant correlation was observed for PPARgamma with free FA (FFA)-AUC in the FCHL group, and an inverse correlation with serum triglycerides (TG) in the control subjects. Although no difference in adipose tissue gene expression of C3, HSL, or PPARgamma was observed between the FCHL patients and the control subjects, several significant correlations were observed between the mRNA levels and FCHL-related metabolic parameters. Thus, the genes of C3, HSL, and PPARgamma may exert a modifying effect on lipid and glucose metabolism in FCHL. However, defects in adipose tissue expression of these genes are not likely to play a primarily role in the pathogenesis of FCHL in Finnish FCHL families.     

Lack of hexose-6-phosphate dehydrogenase impairs lipid mobilization from mouse adipose tissue

In adipose tissue, glucocorticoids regulate lipogenesis and lipolysis. Hexose-6-phosphate dehydrogenase (H6PDH) is an enzyme located in the endoplasmic reticulum that provides a cofactor for the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), regulating the set point of its activity and allowing for tissue-specific activation of glucocorticoids. The aim of this study was to examine the adipose tissue biology of the H6PDH null (H6PDH/KO) mouse. Real-time PCR analysis confirmed similar mRNA levels of 11beta-HSD1 and glucocorticoid receptor-alpha in wild-type (WT) and H6PDH/KO mice in liver and gonadal fat depots. Microsomal 11beta-HSD1 protein levels shown by Western blot analysis corresponded well with mRNA expression in gonadal fat of WT and H6PDH/KO mice. Despite this, the enzyme directionality in these tissues changed from predominately oxoreductase in WT to exclusively dehydrogenase activity in the H6PDH/KO mice. In the fed state, H6PDH/KO mice had reduced adipose tissue mass, but histological examination revealed no difference in average adipocyte size between genotypes. mRNA expression levels of the key lipogenic enzymes, acetyl CoA carboxylase, adiponutrin, and stearoyl-coenzyme A desaturase-2, were decreased in H6PDH/KO mice, indicative of impaired lipogenesis. In addition, lipolysis rates were also impaired in the H6PDH/KO as determined by lack of mobilization of fat and no change in serum free fatty acid concentrations upon fasting. In conclusion, in the absence of H6PDH, the set point of 11beta-HSD1 enzyme activity is switched from predominantly oxoreductase to dehydrogenase activity in adipose tissue; as a consequence, this leads to impairment of fat storage and mobilization.     

Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.     

Fatty acid metabolism and insulin secretion in pancreatic beta cells

Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acyl-CoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial -oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states.Abbreviations ACS acyl-CoA synthetase - ACC acetyl-CoA carboxylase - BAT brown adipose tissue - CPT carnitine palmitoyl transferase - CL citrate lyase - DAG diacylglycerol - GSIS glucose-stimulated insulin secretion - HSL hormone-sensitive lipase - K_ATP ATP-sensitive K⁺ channel - LC-CoA long chain acyl-CoA - PA phosphatidate - PFK-1 phosphofructokinase-1 - PKC protein kinase C - PMA phorbol myristate acetate - PC pyruvate carboxylase - PS phosphatidylserine - SNAP soluble NSF-associated protein - SNAP-25 synaptosomal-associated protein of 25 kD - t-SNARE target SNAP receptor - v-SNARE vesicle SNAP receptor - VAMP vesicle-associated membrane protein - VDCC voltage-dependent Ca²⁺ channel - WAT white adipose tissue     

The effects of glucocorticoids on adipose tissue lipid metabolism

Glucocorticoids (GCs) have long been accepted as being catabolic in nature, liberating energy substrates during times of stress to supply the increased metabolic demand of the body. The effects of GCs on adipose tissue metabolism are conflicting, however, because patients with elevated GCs present with central adiposity. We performed an extensive literature review of the effects of GCs on adipose tissue metabolism. The contradictory effects of GCs on lipid metabolism occur through a number of different mechanisms, some of which are well defined and others remain to be elucidated. Firstly, through increases in caloric and dietary fat intake, along with increased hydrolysis of circulating triglycerides (chylomicrons, very low-density lipoproteins) by lipoprotein lipase activity, GCs increase the amount of fatty acids in circulation, which are then available for ectopic fat distribution (liver, muscle, and central adipocytes). Glucocorticoids also increase de novo lipid production in hepatocytes through increased expression of fatty acid synthase. There is some controversy as to whether these same mechanisms occur in adipocytes, thereby contributing to adipose hypertrophy. Glucocorticoids promote preadipocyte conversion to mature adipocytes, causing hyperplasia of the adipose tissue. Glucocorticoids also have acute antilipolytic effect on adipocytes, whereas their genomic actions facilitate increased lipolysis after about 48 hours of exposure. The acute and long-term effects of GCs on adipose tissue lipolysis remain unclear. Although considerable evidence supports the notion that GCs increase lipolysis through glucocorticoid-induced increases of lipase expression, they clearly have antilipolytic effects within these same tissues and cell line models.     

Fasting energy homeostasis in mice with adipose deficiency of desnutrin/adipose triglyceride lipase

Adipose triglyceride lipase (ATGL) catalyzes the first step of lipolysis of cytoplasmic triacylglycerols in white adipose tissue (WAT) and several other organs. We created adipose-specific ATGL-deficient (ATGLAKO) mice. In these mice, in vivo lipolysis, measured as the increase of plasma nonesterified fatty acid and glycerol levels after injection of a β3-adrenergic agonist, was undetectable. In isolated ATGLAKO adipocytes, β3-adrenergic-stimulated glycerol release was 10-fold less than in controls. Under fed conditions, ATGLAKO mice had normal viability, mild obesity, low plasma nonesterified fatty acid levels, increased insulin sensitivity, and increased daytime food intake. After 5 h of fasting, ATGLAKO WAT showed phosphorylation of the major protein kinase A-mediated targets hormone-sensitive lipase and perilipin A and ATGLAKO liver showed low glycogen and triacylglycerol contents. During a 48-h fast, ATGLAKO mice developed striking and complex differences from controls: progressive reduction of oxygen consumption, high respiratory exchange ratio, consistent with reduced fatty acid availability for energy production, lethargy, hypothermia, and undiminished fat mass, but greater loss of lean mass than controls. Plasma of 48 h-fasted ATGLAKO mice had a unique pattern: low 3-hydroxybutyrate, insulin, adiponectin, and fibroblast growth factor 21 with elevated leptin and corticosterone. ATGLAKO WAT, liver, skeletal muscle, and heart showed increased levels of mRNA related to autophagy and proteolysis. In murine ATGL deficiency, adipose lipolysis is critical for fasting energy homeostasis, and fasting imposes proteolytic stress on many organs, including heart and skeletal muscle.     

Metabolism of lipids in human white adipocyte

Adipose tissue is considered as the body's largest storage organ for energy in the form of triacylglycerols, which are mobilized through lipolysis process, to provide fuel to other organs and to deliver substrates to liver for gluconeogenesis (glycerol) and lipoprotein synthesis (free fatty acids). The release of glycerol and free fatty acids from human adipose tissue is mainly dependent on hormone-sensitive lipase which is intensively regulated by hormones and agents, such as insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). A special attention is paid to the recently discovered perilipins which could regulate the activity of the lipase hormono-sensible. Most of the plasma triacylglycerols are provided by dietary lipids, secreted from the intestine in the form of chylomicron or from the liver in the form of VLDL. Released into circulation as non-esterified fatty acids by lipoprotein lipase, those are taken up by adipose tissue via specific plasma fatty acid transporters (CD36, FATP, FABPpm) and used for triacylglycerol synthesis. A small part of triacylglycerols is synthesized into adipocytes from carbohydrates (lipogenesis) but its regulation is still debated in human. Physiological factors such as dieting/fasting regulate all these metabolic pathways, which are also modified in pathological conditions e.g. obesity.     

Importance of PPAR alpha for the effects of growth hormone on hepatic lipid and lipoprotein metabolism.

OBJECTIVE: Growth hormone (GH) enhances lipolysis in adipose tissue, thereby increasing the flux of fatty acids to other tissues. Moreover, GH increases hepatic triglyceride synthesis and secretion in rats and decreases the action of peroxisome proliferator-activated receptor (PPAR)alpha. PPARalpha is activated by fatty acids and regulates hepatic lipid metabolism in rodents. The aim of this study was to investigate the importance of PPARalpha for the effects of GH on hepatic gene expression and lipoprotein metabolism. DESIGN: Bovine GH was given as a continuous infusion (5mg/kg/day) for 7 days to PPARalpha-null and wild-type (wt) mice. Plasma and liver lipids and hepatic gene expression were measured. In separate experiments, hepatic triglyceride secretion was measured. RESULTS: GH treatment decreased hepatic triglyceride content and increased hepatic triglyceride secretion rate and serum cholesterol levels. Furthermore, GH increased hepatic acylCoA:diacylglycerol acyltransferase (DGAT)2 mRNA levels, but decreased the hepatic mRNA expression of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase and PPARgamma1. All these GH effects were independent of PPARalpha. However, the effect of GH on Cyp4a10, PPARgamma2, and DGAT1 was different between the genotypes. GH treatment decreased Cyp4a10 mRNA expression in wt mice, but increased the expression in PPARalpha-null mice. In contrast, GH decreased the expression of DGAT1 and PPARgamma2 in PPARalpha-null mice, but not in wt mice. CONCLUSIONS: Most of the effects of GH on lipid and lipoprotein metabolism were independent of PPARalpha. However, GH had unique effects on Cyp4a10, DGAT1, and PPARgamma2 gene expression in PPARalpha-null mice showing cross-talk between GH and PPARalpha signalling in vivo.     

Effects of food restriction on peroxisome proliferator-activated receptor-gamma and glucocorticoid receptor signaling in adipose tissues of normal rats

In adipocytes, peroxisome proliferator-activated receptor (PPAR)-gamma activates adipocyte differentiation and glucocorticoid (GC) stimulates the expression of PPAR-gamma mRNA. The local tissue concentrations of GC, in turn, are modulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). To clarify the change of energy metabolism in condition of reduced energy intake, we investigated whether food restriction alters the adipocyte size and levels of PPAR-gamma, GC receptor (GR), and 11beta-HSD1 mRNA expression in the white adipose tissues of normal rats. Male Wistar rats weighing 340 g were housed under free feeding or 20% reduction of food intake for 2 or 14 days. We found that 2-day food restriction did not cause any change in the mean size or number of adipocytes in the omentum, while 14-day food restriction decreased the size and increased the number of adipocytes. In addition, the levels of PPAR-gamma2, GR, and 11beta-HSD1 mRNA expression in the omentum were lower in the food-restricted rats after 2 days, while they did not differ after 14 days. Also, after both 2 and 14 days, plasma concentrations of free fatty acid (FFA) were higher in the food-restricted rats than in control rats. Finally, plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were the same in the both groups after 2 days, although they were higher in the food-restricted rats after 14 days. These results suggest that adipocyte differentiation in the omentum of food-restricted rats is attenuated after 2 days but recovers after 14 days, resulting in an increase in the number of small adipocytes. It is also likely that lipolysis induced during the 14-day period of food restriction decreased the size of adipocytes. Further, food restriction may affect the efficiency of local GC effects by altering GR and 11beta-HSD1 mRNA expression. Also, higher levels of plasma GC and recovery of GR and 11beta-HSD1 mRNA expression may contribute to the recovery of the levels of PPAR-gamma2 mRNA expression in the omentum and result in the recovery of adipocyte differentiation.     

A novel promoter for the 11beta-hydroxysteroid dehydrogenase type 1 gene is active in lung and is C/EBPalpha independent

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) increases intracellular glucocorticoid action by converting inactive to active glucocorticoids (cortisol, corticosterone) within cells. It is highly expressed in glucocorticoid target tissues including liver and lung, and at modest levels in adipose tissue and brain. A selective increase in adipose 11beta-HSD1 expression occurs in obese humans and rodents and is likely to be of pathogenic importance in the metabolic syndrome. Here we have used 5' rapid amplificaiton of cDNA ends (RACE) to identify a novel promoter, P1, of the gene encoding 11beta-HSD1. P1 is located 23 kb 5' to the previously described promoter, P2. Both promoters are active in liver, lung, adipose tissue, and brain. However, P1 (encoding exon 1A) predominates in lung and P2 (encoding exon 1B) predominates in liver, adipose tissue, and brain. Adipose tissue of obese leptin-deficient C57BL/6J-Lepob mice showed higher expression only of the P2-associated exon 1B-containing 11beta-HSD1 mRNA variant. In contrast to P2, which is CAAAT/enhancer binding protein (C/EBP)-alpha inducible in transiently transfected cells, the P1 promoter was unaffected by C/EBPalpha in transfected cells. Consistent with these findings, mice lacking C/EBPalpha had normal 11beta-HSD1 mRNA levels in lung but showed a dramatic reduction in levels of 11beta-HSD1 mRNA in liver and brown adipose tissue. These results therefore demonstrate tissue-specific differential regulation of 11beta-HSD1 mRNA through alternate promoter usage and suggest that increased adipose 11beta-HSD1 expression in obesity is due to a selective increase in activity of the C/EBPalpha-regulated P2 promoter.     

Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis.

Catecholamines and natriuretic peptides stimulate human adipocyte lipolysis through an increase in cAMP and cGMP levels, resulting in phosphorylation and activation of hormone-sensitive lipase. A defect in hormone-sensitive lipase expression might contribute to the resistance to catecholamine-induced lipolysis observed in obesity. The respective roles and regulation of hormone-sensitive lipase and adipose triglyceride lipase in spontaneous and hormone-stimulated lipolysis remain to be determined. Tumor necrosis factor alpha stimulates triglyceride hydrolysis by multiple intracellular pathways acting on insulin signaling, G proteins and perilipins, and might contribute to enhanced plasma fatty acid levels in obesity. Characterization of the lipolytic pathways might provide novel strategies to decrease free fatty acid production and reverse insulin resistance and other obesity-related metabolic complications.     

Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism

CONTEXT: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). EVIDENCE ACQUISITION: Articles on the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990-2006). EVIDENCE SYNTHESIS: Articles were assessed to provide a comprehensive overview of how PPARgamma-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. CONCLUSIONS: PPARgamma is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARgamma activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFalpha, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARgamma also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARgamma activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARgamma-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.     

The effects of thiazolidinedione treatment on the regulations of aquaglyceroporins and glycerol kinase in OLETF rats

Aquaporins (AQPs) that transport glycerol in addition to water are classified as aquaglyceroporins (AQP3, 7, 9). AQP7 in the adipose tissue and AQP9 in the liver may coordinately contribute to the increase in hepatic gluconeogenesis in states of insulin resistance. Thiazolidinedione (TZD) has been shown to increase adipose AQP7 and induce glycerol kinase (GlyK) which is nearly absent in adipocytes. In the present study, we analyzed both GlyK and AQP gene expression in adipose and hepatic tissues, and AQP3 in kidneys from Long-Evans Tokushima Otsuka (LETO), Otsuka Long-Evans Tokushima Fatty (OLETF), and rosiglitazone (RSG)-treated OLETF (RSG-OLETF) rats. We also evaluated AQP9 protein expression in cultured human hepatoma cells treated with oleic acid, Wy14643, or RSG. A 2-week RSG treatment increased AQP7 mRNA levels in the mesenteric fat, but not in the epididymal fat of OLETF rats. Rosiglitazone treatment markedly increased GlyK expression in both fat depots, with a greater increase in the mesenteric fat. The magnitudes of GlyK induction by RSG were greater than that of AQP7 in both adipose tissues (P < .05, each). AQP9 and GlyK levels in the liver were not affected by RSG treatment in OLETF rats. Oleic acid and Wy14643 upregulated AQP9 protein expression in cultured human hepatoma cells in a dose-dependent manner. AQP3 mRNA levels tended to increase in the outer medulla of the RSG-OLETF rats. These results indicate that in the adipose tissue TZD has an important role in the glycerol metabolic pathway through the regulation of AQP and GlyK, especially by GlyK induction. Free fatty acids may directly enhance glycerol availability in the liver via the upregulation of AQP9 levels. Renal AQP3 may be related to the fluid retention caused by TZD.     

Preeclampsia is associated with compromised maternal synthesis of long-chain polyunsaturated Fatty acids, leading to offspring deficiency

Obesity and excessive lipolysis are implicated in preeclampsia (PE). Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with PE (n=62) or intrauterine growth restriction (n=23) compared with healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid-metabolizing enzymes and placental fatty acid transporters were compared. Mothers with PE had higher plasma triglyceride (21%, P<0.001) and nonesterified fatty acid (50%, P<0.001) concentrations than controls. Concentrations of major n-6 and n-3 long-chain polyunsaturated fatty acids in erythrocytes were 23% to 60% lower (all P<0.005) in PE and intrauterine growth restriction mothers and offspring compared with controls. Subcutaneous adipose tissue Δ-5 and Δ-6 desaturase and very long-chain fatty acid elongase mRNA expression was lower in PE than controls (respectively, mean [SD] control 3.38 [2.96] versus PE 1.83 [1.91], P=0.030; 3.33 [2.25] versus 1.03 [0.96], P<0.001; 0.40 [0.81] versus 0.00 [0.00], P=0.038 expression relative to control gene [square root]). Low maternal and fetal long-chain polyunsaturated fatty acid concentrations in PE may be the result of decreased maternal synthesis.     

Effects of cimaterol, a beta-adrenergic agonist, on lipid metabolism in rats

Rats fed a high carbohydrate diet containing 10 or 100 ppm cimaterol for 4 weeks gained 41% to 59% less fat and 70% to 76% more protein than controls, with no major changes in either energy gain or efficiency of energy retention. Effects of cimaterol on lipid metabolism in these rats were assessed. Cimaterol stimulated lipolysis in vivo and in vitro, but failed to influence rates of de novo fatty acid synthesis in either liver or white adipose tissue. Activities of fatty acid synthetase and malic enzyme in these tissues were also unaffected by cimaterol. Cimaterol administered in vivo failed to affect lipoprotein lipase activity in white adipose tissue, but elevated enzyme activity 67% to 75% in the extensor digitorium longus muscle. Lipoprotein lipase activity in the extensor digitorum longus muscle was also elevated by 66% during a 2 hour incubation with 1 mmol/L cimaterol. We conclude that cimaterol selectively stimulates both lipolysis in white adipose tissue and lipoprotein lipase activity in skeletal muscle, to direct energy away from adipose tissue deposition toward skeletal muscle accretion.