Lipogenesis In Adipose Tissue Research Articles

Increased obesity resistance and insulin sensitivity in mice lacking the isocitrate dehydrogenase 2 gene

Reactive oxygen species (ROS) are a byproduct of normal metabolism and play important roles in cell signaling and homeostasis. Mitochondria, the main organelles involved in intracellular ROS production, play central roles in modulating redox-dependent cellular processes such as metabolism and apoptosis. We recently reported an important role for mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) in cellular redox regulation. Here, we show that mice with targeted disruption of IDH2 exhibit resistance to obesity, with lower body weight and reduced visceral fat, and increased insulin sensitivity accompanied by enhanced energy expenditure relative to controls. This function of IDH2 is linked to its capacity to suppress lipogenesis in visceral adipose tissue, partly via transcriptional repression of SREBP1, and to increase thermogenesis in adipocytes by transcriptional activation of UCP1 via activation of the p38 signaling axis. Our results highlight the importance of redox balance in the regulation of metabolism and demonstrate that IDH2 plays a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing this protein as a potential therapeutic target in the treatment of type 2 diabetes and obesity.

Nutrient Regulation: Conjugated Linoleic Acid's Inflammatory and Browning Properties in Adipose Tissue.

Obesity is the most widespread nutritional disease in the United States. Developing effective and safe strategies to manage excess body weight is therefore of paramount importance. One potential strategy to reduce obesity is to consume conjugated linoleic acid (CLA) supplements containing isomers cis-9, trans-11 and trans-10, cis-12, or trans-10, cis-12 alone. Proposed antiobesity mechanisms of CLA include regulation of (a) adipogenesis, (b) lipid metabolism, (c) inflammation, (d) adipocyte apoptosis, (e) browning or beiging of adipose tissue, and (f) energy metabolism. However, causality of CLA-mediated responses to body fat loss, particularly the linkage between inflammation, thermogenesis, and energy metabolism, is unclear. This review examines whether CLA's antiobesity properties are due to inflammatory signaling and considers CLA's linkage with lipogenesis, lipolysis, thermogenesis, and browning of white and brown adipose tissue. We propose a series of questions and studies to interrogate the role of the sympathetic nervous system in mediating CLA's antiobesity properties.

Fructose and stress induce opposite effects on lipid metabolism in the visceral adipose tissue of adult female rats through glucocorticoid action.

Daily exposure to stress and excessive fructose intake coincides with the growing rate of obesity and related disorders, to which women are more prone than men. Glucocorticoids, the main regulators of energy balance and response to stress, have been associated with the development of metabolic disturbances. The aim of the present study was to examine the effects of fructose overconsumption and/or chronic stress on glucocorticoid signalization and lipid metabolism in female rat adipose tissue. We examined the effects of fructose-enriched diet and chronic unpredictable stress, separately and in combination, on glucocorticoid signaling in terms of 11β-hydroxysteroid dehydrogenase 1 (HSD1)-catalyzed corticosterone regeneration, glucocorticoid receptor (GR) intracellular distribution, hormone binding and transcriptional regulation of genes involved in lipolysis (hormone-sensitive lipase) and lipogenesis (lipoprotein lipase, acetyl-CoA carboxylase, fatty acid synthase and phosphoenolpyruvate carboxykinase) in the visceral adipose tissue (VAT) of adult female rats. Additionally, the nuclear level of the peroxisomal proliferator-activated receptor γ (PPARγ) was analyzed. The combination of stress and fructose-enriched diet led to an elevation in HSD1 expression and intracellular corticosterone concentration, whereas GR nuclear accumulation was enhanced after separate treatments. Furthermore, fructose was shown to induce the expression of all examined lipogenic genes and nuclear accumulation of PPARγ, thereby stimulating adipogenesis, while stress upregulated HSL, reducing the adipose tissue mass regardless of fructose consumption. Prolonged overconsumption of fructose and chronic exposure to stress promote opposite effects on lipid metabolism in the VAT of adult female rats and suggest that these effects could be mediated by glucocorticoids.

Unraveling the Paradox of Selective Insulin Resistance in the Liver: the Brain–Liver Connection

The insulin receptor (IR) is expressed widely throughout the brain (1); however, unlike insulin in peripheral tissues whose major function is regulation of glucose metabolism, the actions of insulin in the brain are less glucocentric. Glucose enters neurons and glia of the brain primarily through the facilitative glucose transporters GLUT1 and GLUT3 (2), which are not insulin dependent. Despite being dispensable for glucose entry into the brain, early work by Woods et al. (3) and others (reviewed in ref. 1) demonstrated that intracerebroventricular (ICV) delivery of insulin into the brain could produce a multitude of effects, including suppression of feeding behavior and hepatic glucose production, activation of thermogenesis in brown adipose tissue, and stimulation of lipogenesis in white adipose tissue, all without significantly altering systemic insulin levels. Using a conditional knockout of the IR in the brain, Bruning and colleagues (4,5) demonstrated that the actions of insulin in the brain require IRs and can produce a range of phenotypes including mild obesity, decreased counterregulatory responsiveness to hypoglycemia, and hypothalamic hypogonadism. This has been confirmed and refined by region-specific IR knockouts and knockdowns of the IR using antisense technology (6,7). Studies using animal models and in vitro systems have uncovered many other …

α 1-acid glycoprotein inhibits lipogenesis in neonatal swine adipose tissue

Serum α1-acid glycoprotein (AGP) is elevated during late gestation and at birth in the pig and rapidly declines postnatally. In contrast, the pig is born with minimal lipid stores in the adipose tissue, but rapidly accumulates lipid during the first week. The present study examined if AGP can affect adipose tissue metabolism in the neonatal pig. Isolated cell cultures or tissue explants were prepared from dorsal subcutaneous adipose tissue of preweaning piglets. Porcine AGP was used at concentrations of 0, 100, 1000 and 5000 ng/ml medium in 24 h incubations. AGP reduced the messenger RNA (mRNA) abundance of the lipogenic enzymes, malic enzyme (ME), fatty acid synthase and acetyl coA carboxylase by at least 40% (P<0.001). The activity of ME and citrate lyase were also reduced by AGP (P<0.05). Glucose oxidation was reduced by treatment with 5000 ng AGP/ml medium (P<0.05). The 14C-glucose incorporation into fatty acids was reduced by ~25% by AGP treatment for 24 h with 1000 ng AGP/ml medium (P<0.05). The decrease in glucose metabolism by AGP appears to function through an inhibition in insulin-mediated glucose oxidation and incorporation into fatty acids. This was supported by the analysis of the mRNA abundance for sterol regulatory element-binding protein (SREBP), carbohydrate regulatory element-binding protein (ChREBP) and insulin receptor substrate 1 (IRS1), which all demonstrated reductions of at least 23% in response to AGP treatment (P<0.05). These data demonstrate an overall suppression of lipogenesis due to AGP inhibition of lipogenic gene expression in vitro, which the metabolic data and SREBP, ChREBP and IRS1 gene expression analysis suggest is through an inhibition in insulin-mediated events. Second, these data suggest that AGP may contribute to limiting lipogenesis within adipose tissue during the perinatal period, as AGP levels are highest for any serum protein at birth.

Transcriptional regulation of acetyl-CoA carboxylase α isoforms in dairy ewes during conjugated linoleic acid induced milk fat depression

Feeding trans-10, cis-12 CLA to lactating ewes reduces milk fat by down-regulating expression of enzymes involved in lipid synthesis in the mammary gland and increases adipose tissue lipogenesis. Acetyl-CoA carboxylase α (ACC-α) is a key regulated enzyme in de novo fatty acid synthesis and is decreased by CLA. In the ovine, the ACC-α gene is expressed from three tissue-specific promoters (PI, PII and PIII). This study evaluated promoter-specific ACC-α expression in mammary and adipose tissue of lactating cross-bred Lacaune/Texel ewes during milk fat depression induced by rumen-unprotected trans-10, cis-12 CLA supplement. In all, 12 ewes arranged in a completely randomized design were fed during early, mid and late lactation one of the following treatments for 14 days: Control (forage+0.9 kg of concentrate on a dry matter basis) and CLA (forage+0.9 kg of concentrate+27 g/day of CLA (29.9% trans-10, cis-12)). Mammary gland and adipose tissue biopsies were taken on day 14 for gene expression analysis by real-time PCR. Milk fat yield and concentration were reduced with CLA supplementation by 27%, 21% and 35% and 28%, 26% and 42% during early, mid and late lactation, respectively. Overall, our results suggest that trans-10, cis-12 CLA down-regulates mammary ACC-α gene expression by decreasing expression from PII and PIII in mammary gland and up-regulates adipose ACC-α gene expression by increasing expression from PI.

Hypoxia is associated with a lower expression of genes involved in lipogenesis in visceral adipose tissue.

BackgroundA key role for HIF-1α in the promotion and maintenance of dietary obesity has been proposed. We analyzed the association between hypoxia and de novo lipogenesis in human adipose tissue.MethodsWe studied HIF-1α mRNA and protein expression in fasting status in visceral adipose tissue (VAT) from non-obese and morbidly obese subjects, and in VAT from wild-type and ob/ob C57BL6J mice in both fasting and feeding status. We also analyzed the effect of hypoxia on the VAT mRNA expression of genes involved in lipogenesis.ResultsHIF-1α was increased in VAT from morbidly obese subjects. In fasting status, C57BL6J ob/ob mice had a higher VAT HIF-1α mRNA expression than C57BL6J wild-type mice. In feeding status, VAT HIF-1α mRNA expression significantly increased in C57BL6J wild-type, but not in C57BL6J ob/ob mice. In humans, HIF-1α mRNA expression correlated positively with body mass index and insulin resistance. VAT HIF-1α mRNA expression correlated negatively with ACC1, PDHB and SIRT3 mRNA expression, and positively with PPAR-γ. VAT explants incubated in hypoxia showed reduced SIRT3 and increased PPAR-γ, SREBP-1c, ACLY, ACC1 and FASN mRNA expression.ConclusionsMorbidly obese subjects have a higher level of VAT HIF-1α. Postprandial status is associated with an increase in HIF-1α mRNA expression in C57BL6J wild-type mice. Hypoxia alters the mRNA expression of genes involved in de novo lipogenesis in human VAT.

Early redox imbalance is associated with liver dysfunction at weaning in overfed rats.

Neonatal overfeeding induced by litter size reduction leads to further obesity and other metabolic disorders, such as liver oxidative stress and microsteatosis at adulthood. We hypothesized that overfeeding causes an early redox imbalance at weaning, which could programme the animals to future liver dysfunction. Thus, we studied lipogenesis, adipogenesis, catecholamine status and oxidative balance in weaned overfed pups. To induce early overfeeding, litters were adjusted to three pups at the 3rd day of lactation (SL group). The control group contained 10 pups per litter until weaning (NL group). Peripheral autonomic nerve function was determined in vivo at 21 days old. Thereafter, pups were killed for further analysis. Differences were considered significant when P < 0.05. The SL pups presented with a higher visceral adipocyte area, higher content of lipogenic enzymes (ACC, FAS) and with a lower content of adipogenic factors (CEBP, PPARγ) in visceral adipose tissue (VAT). Although autonomic nerve activity and adrenal catecholamine production were not significantly altered, catecholamine receptor (β3ADR) content was lower in VAT. The SL pups also presented with higher triglyceride, PPARγ, PPARα and PGC1α contents in liver. In plasma and liver, the SL pups showed an oxidative imbalance, with higher lipid peroxidation and protein oxidation. The SL group presented with a higher serum alanine aminotransferase (ALT). The early increase in lipogenesis in adipose tissue and liver in weaned overfed rats suggests that the higher oxidative stress and lower catecholamine content in VAT are associated with the early development of liver dysfunction and adipocyte hypertrophy.

Fatty acid composition of adipose tissue triglycerides in obese diabetic women after bariatric surgery: a 2-year follow up.

Bariatric surgery is the most effective method in the treatment of obesity and type 2 diabetes (T2DM). The aim of this study was to evaluate the effects of different types of bariatric procedures on remission of T2DM and on the fatty acid composition in subcutaneous adipose tissue. Patients included obese diabetic women who underwent bariatric surgery: biliopancreatic diversion (BPD), n=8, laparoscopic gastric banding (LAGB), n=9 or laparoscopic greater curvature plication (LGCP), n=12. Anthropometric characteristics and fatty acid composition of adipose tissue (FA AT) were analyzed before surgery, then 6 months and 2 years after surgery. FA AT was analyzed by gas chromatography. Diabetes remission was estimated. BPD was most efficient in inducing a remission of diabetes (p=0.004). Significantly higher increases in lauric (12:0), myristoleic (14:1n-5) and palmitoleic (16:1n-7) acids and delta-9 desaturase were found two years after BPD, suggesting higher lipogenesis in adipose tissue. Docosatetraenoic acid (22:4n-6) increased significantly after BPD, while docosapentaenoic acid (22:5n-3) decreased 6 months after BPD and increased after 2 years. No changes were found after LAGB and LGCP after 2 years. Bariatric surgery led to significant changes in the fatty acid composition of subcutaneous adipose tissue in severely obese diabetic women after six months and two years, and was partly influenced by the type of surgery used.

Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice

Our objective was to determine if consuming table grapes reduces adiposity and its metabolic consequences and alters gut microbiota in mice fed a high-fat (HF), butter-rich diet. C57BL/6J mice were fed a low-fat (LF) diet or HF diet with 3% or 5% grapes for 11weeks. Total body and inguinal fat were moderately but significantly reduced in mice fed both levels of grapes compared to their controls. Mice fed 5% grapes had lower liver weights and triglyceride levels and decreased expression of glycerol-3-phosphate acyltransferase (Gpat1) compared to the 5% controls. Mice fed 3% grapes had lower hepatic mRNA levels of peroxisome proliferator-activated receptor gamma 2, sterol-CoA desaturase 1, fatty-acid binding protein 4 and Gpat1 compared to the 3% controls. Although grape feeding had only a minor impact on markers of inflammation or lipogenesis in adipose tissue or intestine, 3% of grapes decreased the intestinal abundance of sulfidogenic Desulfobacter spp. and the Bilophila wadsworthia-specific dissimilatory sulfite reductase gene and tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls. In addition, Bifidobacterium, Lactobacillus, Allobaculum and several other genera correlated negatively with adiposity. Allobaculum in particular was increased in the LF and 3% grapes groups compared to the HF-fed controls. Notably, grape feeding attenuated the HF-induced impairment in epithelial localization of the intestinal tight junction protein zonula occludens. Collectively, these data indicate that some of the adverse health consequences of consuming an HF diet rich in saturated fat can be attenuated by table grape consumption.

OR013: Chronic Dietary Exposure to Branched Chain AMINO ACIDS Causes Impaired Glucose Disposal and Higher Adipose Tissue Lipogenesis

OR013: Chronic Dietary Exposure to Branched Chain AMINO ACIDS Causes Impaired Glucose Disposal and Higher Adipose Tissue Lipogenesis

The Glucose Sensor ChREBP Links De Novo Lipogenesis to PPARγ Activity and Adipocyte Differentiation.

Reduced de novo lipogenesis in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here, we report that carbohydrate-response element-binding protein (ChREBP), a transcriptional inducer of glucose use and de novo lipogenesis, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)γ. Expression of constitutive-active ChREBP in precursor cells activated endogenous PPARγ and promoted adipocyte differentiation. Intriguingly, ChREBP-constitutive-active ChREBP expression induced PPARγ activity in a fatty acid synthase-dependent manner and by trans-activating the PPARγ ligand-binding domain. Reducing endogenous ChREBP activity by either small interfering RNA-mediated depletion, exposure to low-glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARγ target genes, in particular those involved in thermogenesis, similar to synthetic PPARγ ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARγ. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARγ.

A Methionine Deficient Diet Enhances Adipose Tissue Lipid Metabolism and Alters Anti-Oxidant Pathways in Young Growing Pigs.

Methionine is a rate-limiting amino-acid for protein synthesis but non-proteinogenic roles on lipid metabolism and oxidative stress have been demonstrated. Contrary to rodents where a dietary methionine deficiency led to a lower adiposity, an increased lipid accretion rate has been reported in growing pigs fed a methionine deficient diet. This study aimed to clarify the effects of a dietary methionine deficiency on different aspects of tissue lipid metabolism and anti-oxidant pathways in young pigs. Post-weaned pigs (9.8 kg initial body weight) were restrictively-fed diets providing either an adequate (CTRL) or a deficient methionine supply (MD) during 10 days (n=6 per group). At the end of the feeding trial, pigs fed the MD diet had higher lipid content in subcutaneous adipose tissue. Expression levels of genes involved in glucose uptake, lipogenesis but also lipolysis, and activities of NADPH enzyme suppliers were generally higher in subcutaneous and perirenal adipose tissues of MD pigs, suggesting an increased lipid turnover in those pigs. Activities of the anti-oxidant enzymes superoxide dismutase, catalase and glutathione reductase were increased in adipose tissues and muscle of MD pigs. Expression level and activity of the glutathione peroxidase were also higher in liver of MD pigs, but hepatic contents in the reduced and oxidized forms of glutathione and glutathione reductase activity were lower compared with control pigs. In plasma, superoxide dismutase activity was higher but total anti-oxidant power was lower in MD pigs. These results show that a dietary methionine deficiency resulted in increased levels of lipogenesis and lipolytic indicators in porcine adipose tissues. Decreased glutathione content in the liver and coordinated increase of enzymatic antioxidant activities in adipose tissues altered the cellular redox status of young pigs fed a methionine-deficient diet. These findings illustrate that a rapidly growing animal differently adapts tissue metabolisms when facing an insufficient methionine supply.

Inhibition of the lipogenesis in liver and adipose tissue of diet-induced obese C57BL/6 mice by feeding oleic acid-rich sesame oil

The effects of sesame oil (SO) on lipogenic gene expression and lipid metabolism were observed. One percent of SO was added into the high-fat diet (HFD) used to feed C57BL/6 male mice for 8 weeks. SO significantly lowered adipose tissue mass than that of the high-fat control group. In addition, serum and hepatic lipid contents were markedly lower than those of the high-fat control group. Especially, the ratio of HDL/LDL was much higher than that of the HFD group. The gene expression of key lipogenic enzymes, Ppar-γ, Srebp-1c, Scd-1, Fas, Acc, Lpl, and malic enzyme, was significantly downregulated in the liver and adipose tissue of mice fed sesame oil. This study suggests that high proportion of oleic acid in SO might be strongly associated with lowering serum and hepatic lipid profile and suppressing lipogenic gene expression.

A major role of insulin in promoting obesity-associated adipose tissue inflammation

ObjectiveAdipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation.MethodsCirculating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored. Conversely, insulin was infused into lean mice to determine its affects on the above parameters.ResultsLowering circulating insulin levels in obese mice by streptozotocin treatment decreased macrophage content in AT, enhancing insulin stimulated Akt phosphorylation and de novo lipogenesis (DNL). Moreover, responsiveness of blood glucose levels to injected insulin was improved by streptozotocin and diazoxide treatments of obese mice without changes in body weight. Remarkably, even in lean mice, infusion of insulin under constant euglycemic conditions stimulated expression of cytokines in AT. Consistent with these findings, insulin treatment of 3T3-L1 adipocytes caused a 10-fold increase in CCL2 mRNA levels within 6 h, which was blocked by the ERK inhibitor PD98059.ConclusionTaken together, these results indicate that obesity-associated hyperinsulinemia unexpectedly drives AT inflammation in obese mice, which in turn contributes to factors that suppress insulin-stimulated adipocyte DNL and systemic insulin sensitivity.

Influence of crude extract and bioactive fractions of Ilex paraguariensis A. St. Hil. (yerba mate) on the Wistar rat lipid metabolism

The influence of yerba mate extract (YME) and two concentrated fractions of methylxanthines–polyphenols (MXPL) and saponins (SFL) from yerba mate on the lipid metabolism of Wistar rats fed with a high-fat diet were examined. A Box–Behnken design was employed for the optimization of yerba mate extraction. Subsequently, one-step separation using solid phase fractionation was applied. HPLC–PDA and UPLC/Q-TOF-MS were used for quantification and identification of the main compounds. YME induced reductions on intra-abdominal fat weight gain and LDL plasma level. MXPL decreased plasma levels of cholesterol, LDL and triacylglycerols. In addition, this fraction increased lipogenesis of the muscle, hepatic glycogen synthesis and lipolysis in adipose tissue. SFL enhanced lipogenesis in adipose tissue and also fecal fat excretion comparing to both controls. Moreover, all mate preparations could entirely revert the hepatic lipogenesis induced by the high-fat diet. Thus, the yerba mate extract and fractions exhibited a potential anti-obesity effect on lipid metabolism of the Wistar rat and deserve further investigation.

A combination of probiotics and whey proteins enhances anti-obesity effects of calcium and dairy products during nutritional energy restriction in aP2-agouti transgenic mice.

Lactobacillus rhamnosus GG, Lactobacillus paracasei TMC0409, Streptococcus thermophilus TMC1543 and whey proteins were used to prepare fermented milk. For the experiment aP2- agouti transgenic mice were pre-treated with a high-sucrose/high-fat diet for 6 weeks to induce obesity. The obese mice were fed a diet containing 1·2% Ca and either non-fat dried milk (NFDM) or probiotic-fermented milk (PFM) with nutritional energy restriction for 6 weeks. The animals were examined after the treatment for changes in body weight, fat pad weight, fatty acid synthase (FAS) activity, lypolysis, the expression levels of genes related to lipid metabolism, insulin sensitivity in adipocytes and skeletal muscle and the presence of biomarkers for oxidative and inflammatory stress in plasma. It was found that the PFM diet significantly reduced body weight, fat accumulation, and adipocyte FAS activity, and increased adipocyte lipolysis as compared with the effects of the NFDM diet (P<0·05). The adipose tissue gene expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) was significantly suppressed in mice that were fed PFM as compared with those that were fed NFDM (P<0·05). PFM caused a greater up-regulation of skeletal muscle PPARα, PPARδ, uncoupling protein 3 (UCP3) and GLUT4 expression and a significant decrease in the plasma concentration of insulin, malondialdehyde, TNF-α, monocyte chemotactic protein-1 and C-reactive protein as compared with the effects of NFDM (P<0·05). Fermentation of milk with selected probiotics and supplementation of milk with whey proteins may thus enhance anti-obesity effects of Ca and dairy products by the suppression of adipose tissue lipogenesis, activation of fat oxidation in skeletal muscle and reduction of oxidative and inflammatory stress.

Regulation of systemic energy homeostasis by serotonin in adipose tissues.

Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis.

Role of Acyl‐Coenzyme A:Cholesterol Acyltransferase 1 in Lipogenesis in Adipocytes

Dysregulated lipogenesis in adipose tissue contributes to obesity and its metabolic disorders. However, the molecular mechanisms regulating lipogenesis in adipocytes are not fully understood. Acyl‐coenzyme A: cholesterol acyltransferase (ACAT), an enzyme that catalyzes the formation of cholesteryl ester from free cholesterol (FC), has been identified as a therapeutic target to treat atherosclerosis. However, the role of ACAT in adipogenesis and lipogenesis in adipocytes is unknown. Here, we employed both pharmaceutical inhibitors and a lentivirus‐mediated shRNA‐based gene knockdown technique to investigate the role of ACAT in adipogenesis using murine 3T3‐L1 preadipocytes as an in vitro model of adipogenesis. Avasimibe, an ACAT inhibitor, was added at non‐toxic concentrations and replaced every other day during the course of adipogenesis. Avasimibe treatment inhibited lipid accumulation in a dose‐dependent manner, as judged by Oil red O staining and thin layer chromatography. Consistently, ACAT1 knockdown in 3T3‐L1 cells reduced lipid droplet accumulation by 40%. Real‐time PCR revealed that ACAT inhibition down‐regulated expressions of sterol regulatory element‐binding protein‐1 and genes involved in lipogenesis, with little effect on adipogenic transcription factors. These results suggest that ACAT is required for lipid droplet biogenesis in adipocytes. In addition, ACAT inhibition reduced 37% of intracellular FC and impaired cholesterol uptake in adipocytes, indicating a role of ACAT1 in the biochemical link between lipogenesis and cholesterol homeostasis. Taken together, our results reveal a novel function of ACAT1 in lipogenesis and highlight an important role of ACAT1 in integrating cholesterol metabolism and neutral lipid synthesis in adipocytes.

Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation

Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues.