Lipogenesis In Brown Adipose Tissue Research Articles

CD36 regulates substrates utilisation in brown adipose tissue of spontaneously hypertensive rats: In vitro study.

Thermogenesis in brown adipose tissue (BAT) uses intracellular triglycerides, circulating free fatty acids and glucose as the main substrates. The objective of the current study was to analyse the role of CD36 fatty acid translocase in regulation of glucose and fatty acid utilisation in BAT. BAT isolated from spontaneously hypertensive rat (SHR) with mutant Cd36 gene and SHR-Cd36 transgenic rats with wild type variant was incubated in media containing labeled glucose and palmitate to measure substrate incorporation and oxidation. SHR-Cd36 versus SHR rats showed significantly increased glucose incorporation into intracellular lipids associated with reduced glycogen synthase kinase 3β (GSK-3β) protein expression and phosphorylation and increased oxidation of exogenous palmitate. It can be concluded that CD36 enhances glucose transport for lipogenesis in BAT by suppressing GSK-3β and promotes direct palmitate oxidation.

High-Fat-Diet Suppressed Ketone Body Utilization for Lipogenic Pathway in Brown Adipose Tissues.

Brown adipose tissue (BAT) consumes excess lipids and produces lipid metabolites as ketone bodies. These ketone bodies are then recycled for lipogenesis by the enzyme acetoacetyl-CoA synthetase (AACS). Previously, we found that a high-fat diet (HFD) upregulated AACS expression in white adipose tissue. In this study, we investigated the effects of diet-induced obesity on AACS in BAT. When 4-week-old ddY mice were fed a HFD or high-sucrose diet (HSD) for 12 weeks, a significant decrease in Aacs, acetyl-CoA carboxylase-1 (Acc-1), and fatty acid synthase (Fas) expression was observed in the BAT of the HFD group, whereas expression was not affected in the HSD group. In vitro analysis showed decreased Aacs and Fas expression in rat primary-cultured brown adipocytes following isoproterenol treatment for 24 h. In addition, the suppression of Aacs by siRNA markedly decreased the expression of Fas and Acc-1 but did not affect the expression of uncoupling protein-1 (UCP-1) or other factors. These results suggested that HFD may suppress ketone body utilization for lipogenesis in BAT and that AACS gene expression may be important for regulating lipogenesis in BAT. Therefore, the AACS-mediated ketone body utilization pathway may regulate lipogenesis under conditions of excess dietary fat.

ChREBP-regulated lipogenesis is not required for the thermogenesis of brown adipose tissue.

ObjectivesBrown adipose tissue (BAT) plays a critical role in energy expenditure by uncoupling protein 1 (UCP1)-mediated thermogenesis and represents an important therapeutic target for metabolic diseases. Carbohydrate response element-binding protein (ChREBP) is a key transcription factor regulating de novo lipogenesis, and its activity is associated with UCP1 expression and thermogenesis in BAT. However, the exact physiological role of endogenous ChREBP in BAT thermogenesis remains unclear.MethodsWe used the Cre/LoxP system to generate ChREBP BAT-specific knockout mice, and examined their BAT thermogenesis under acute cold exposure and long-term cold acclimation. Gene expression was analyzed at the mRNA and protein levels, and lipogenesis was examined by 3H-H2O incorporation assay.ResultsThe mice lacking ChREBP specifically in BAT displayed a significant decrease in the expression levels of lipogenic genes and the activity of de novo lipogenesis in BAT after cold exposure, with UCP1 expression decreased under thermoneutral conditions or after acute cold exposure but not chronic cold acclimation. Unexpectedly, BAT-specific ChREBP deletion did not significantly affect body temperature as well as local temperature or morphology of BAT after acute cold exposure or chronic cold acclimation. Of note, ChREBP deletion mildly aggravated glucose intolerance induced by a high-fat diet.ConclusionsOur work indicates that ChREBP regulates de novo lipogenesis in BAT and glucose tolerance, but is not required for non-shivering thermogenesis by BAT under acute or long-term cold exposure.

A new role for lipocalin prostaglandin d synthase in the regulation of brown adipose tissue substrate utilization.

In this study, we define a new role for lipocalin prostaglandin D synthase (L-PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator–activated receptor γ coactivator 1α or 1β and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis and de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knockout mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L-PGDS plays an important role in the regulation of glucose utilization in vivo.

Effect of hydrazine on liver and brown adipose tissue lipogenesis in 24 h-starved rats.

Journal Article Effects of hydrazine on liver and brown adipose tissue lipogenesis in 24 h-starved rats Get access C E Marshall, C E Marshall Department of Surgery, Charing Cross Hospital Medical School, Fulham Palace Road, Hammersmith, London W6 8RF Correspondence. Department of Surgery, Charing Cross Hospital Medical School, Fulham Palace Road, Hammersmith, London W6 8RF Search for other works by this author on: Oxford Academic Google Scholar D I Watts, D I Watts Department of Chemical Pathology, London Hospital Medical School, Turner Street, London E1 2AD, U.K. Search for other works by this author on: Oxford Academic Google Scholar M C Sugden M C Sugden Department of Chemical Pathology, London Hospital Medical School, Turner Street, London E1 2AD, U.K. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 35, Issue 7, July 1983, Pages 460–461, https://doi.org/10.1111/j.2042-7158.1983.tb04323.x Published: 12 April 2011 Article history Received: 30 November 1982 Published: 12 April 2011

White adipose tissue re-growth after partial lipectomy in high fat diet induced obese Wistar rats

The effects of partial removal of epididymal (EPI) and retroperitoneal (RET) adipose tissues (partial lipectomy) on the triacylglycerol deposition of high fat diet induced obese rats were analyzed, aiming to challenge the hypothesized body fat regulatory system. Male 28-day-old wistar rats received a diet enriched with peanuts, milk chocolate and sweet biscuits during the experimental period. At the 90th day of life, rats were submitted to either lipectomy (L) or sham surgery. After 7 or 30 days, RET, EPI, liver, brown adipose tissue (BAT), blood and carcass were obtained and analyzed. Seven days following surgery, liver lipogenesis rate and EPI relative weight were increased in L. After 30 days, L, RET and EPI presented increased lipogenesis, lipolysis and percentage of small area adipocytes. L rats also presented increased liver malic enzyme activity, BAT lipogenesis, and triacylglycerol and corticosterone serum levels. The partial removal of visceral fat pads affected the metabolism of high fat diet obese rats, which leads to excised tissue re-growth and possibly compensatory growth of non-excised depots at a later time.

PPARγ differentially regulates energy substrate handling in brown vs. white adipose: focus on “The PPARγ agonist rosiglitazone enhances rat brown adipose tissue lipogenesis from glucose without altering glucose uptake”

peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor and ligand-activated transcription factor that is highly expressed in brown adipose tissue (BAT) and is necessary for its development ([1][1], [6][2], [7][3]). BAT is well recognized for its functions in metabolic rate

The PPARγ agonist rosiglitazone enhances rat brown adipose tissue lipogenesis from glucose without altering glucose uptake

We investigated the mechanisms whereby peroxisome proliferator-activated receptor-gamma (PPARgamma) agonism affects glucose and lipid metabolism in brown adipose tissue (BAT) by studying the impact of PPARgamma activation on BAT glucose uptake and metabolism, lipogenesis, and mRNA levels plus activities of enzymes involved in triacylglycerol (TAG) synthesis. Interscapular BAT of rats treated or not with rosiglitazone (15 mg*kg(-1).day(-1), 7 days) was evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (PAP or lipin-1), and diacylglycerol acyltransferase (DGAT). Rosiglitazone increased BAT mass without affecting whole tissue glucose uptake. BAT glycogen content (-80%), its synthesis from glucose (-50%), and mRNA levels of UDP-glucose pyrophosphorylase (-40%), which generates UDP-linked glucose for glycogen synthesis, were all reduced by rosiglitazone. In contrast, BAT TAG-glycerol synthesis in vivo and glucose incorporation into TAG-glycerol in vitro were stimulated by the agonist along with the activities and mRNA levels of glycerol 3-phosphate-generating phosphoenolpyruvate carboxykinase and glycerokinase. Furthermore, rosiglitazone markedly increased the activities of GPAT and DGAT but not those of lipin-1-mediated PAP-1, enzymes involved in the sequential acylation of glycerol 3-phosphate and TAG synthesis. Because an adequate supply of fatty acids is essential for BAT nonshivering thermogenesis, the enhanced ability of BAT to synthesize TAG under PPARgamma activation may constitute an important mechanism by which lipid substrates are stored in preparation for an eventual thermogenic activation.

Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis.

The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3',5-triiodothyronine (T3), the disruption of which (Dio2(-/-)) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2(-/-) BAT sympathetic stimulation approximately 10-fold (normal approximately 4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor gamma coactivator 1, increased well above the levels detected in the cold-exposed wild-type animals. The sustained Dio2(-/-) BAT adrenergic hyperresponse suppressed the three- to fourfold stimulation of BAT lipogenesis normally seen after 24-48 h in the cold. Pharmacological suppression of lipogenesis with betabeta'-methyl-substituted alpha-omega-dicarboxylic acids of C14-C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2(-/-) mice.

Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo.

A survey of genes differentially expressed in the brown adipose tissue (BAT) of mice exposed to a range of environmental temperatures was carried out to identify novel genes and pathways associated with the transition of this tissue toward an amplified thermogenic state. The current report focuses on an analysis of the expression patterns of 50 metabolic genes in BAT under control conditions (22 degrees C), cold exposure (4 degrees C, 1 to 48 h), warm acclimation (33 degrees C, 3 wk), or food restriction/meal feeding (animals fed the same amount as warm mice). In general, expression of genes encoding proteins involving glucose uptake and catabolism was significantly elevated in the BAT of cold-exposed mice. The levels of mRNAs encoding proteins critical to de novo lipogenesis were also increased. Gene expression for enzymes associated with procurement and combustion of long chain fatty acids (LCFAs) was increased in the cold. Thus, a model was proposed in which coordinated activation of glucose uptake, fatty acid synthesis, and fatty acid combustion occurs as part of the adaptive thermogenic processes in BAT. Confirmation emerged from in vivo assessments of cold-induced changes in BAT 2-deoxyglucose uptake (increased 2.7-fold), BAT lipogenesis (2.8-fold higher), and incorporation of LCFA carboxyl-carbon into BAT water-soluble metabolites (elevated approximately twofold). It is proposed that temperature-sensitive regulation of distinct intracellular malonyl-CoA pool sizes plays an important role in driving this unique metabolic profile via maintenance of the lipogenic pool but diminution of the carnitine palmitoyltransferase 1 inhibitory pool under cold conditions.

Aging changes tissue-specific glucose metabolism in rats.

This study defines the tissue-specific changes in glucose metabolic flux that occur over time prior to the onset of whole-body insulin resistance in rats. Rats at 6 weeks of age were maintained on a high-carbohydrate diet for either 12 or 26 weeks, at which time euglycemic clamps were performed at basal and midphysiological plasma insulin concentrations. Following death, insulin-sensitive tissues were excised and frozen until assayed for the rate of glucose uptake, glycogenesis, and lipogenesis. Glucose metabolic flux, particularly through glycogenesis, was reduced between 18 and 32 weeks of age in all tissues except the adipose tissues. For example, the rate of glycogenesis in liver at 18 weeks (117+/-10 nmol glucose incorporated/min/g) was more than double that observed at 32 weeks (54+/-8 nmol glucose incorporated/min/g, P < .01). Despite this, animals in the 32-week group displayed no impairment in whole-body glucose disposal, due to compensatory glucose uptake in white adipose tissue (WAT) and increased glucose flux through lipogenesis in brown adipose tissue (BAT). At 32 weeks, the rate of glucose uptake in WAT (85.0+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g) was approximately double that at 18 weeks (46.6+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g) was approximately double that at 18 weeks (46.6+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g, P < .01). These changes in insulin responsiveness in adipose tissue of older animals may underlie the increased adiposity that is currently thought to be the causative factor in the development of age-related insulin resistance.

Effect of hexachlorobenzene on NADPH-generating lipogenic enzymes and L-glycerol-3-phosphate dehydrogenase in brown adipose tissue.

The effect of the in vivo administration of hexachlorobenzene (HCB) (100 mg/100 g bw) for 30 days, on the activities of brown adipose tissue (BAT) lipogenic enzymes, i.e. malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PD) and the mitochondrial non lipogenic enzyme, L-glycerol-3-phosphate dehydrogenase (LG3PD), was studied in male Wistar rats, submitted to various neurohormonal manipulations. BAT ME, G6PD and LG3PD activities showed significant reductions in response to HCB treatment both in euthyroid and surgically thyroidectomized rats, showing that the effect does not depend on the presence of thyroid hormones. These results differ from those obtained for hepatic ME and G6PD activities, which increased in HCB intoxicated rats without alteration in LG3PD. HCB decreased BAT ME activity under BAT denervation. Administration of HCB resulted in time and dose-dependent decreases in the activity of BAT malic enzyme. The basal activity of ME was increased in hypothyroid rats, while that of LG3PD was reduced. A stimulatory effect of receptor-saturating doses of triiodothyronine (T3) (50 microg/100 g body weight) was observed on BAT ME and LG3PD activities in thyroidectomized rats, showing that the enzymes responded to thyroid hormone stimulation in a normal manner. The stimulatory effect of saturating doses of T3 on ME and LG3PD was reduced by HCB. The results presented herein unequivocally show that brown adipose tissue is a specific target in HCB-induced toxicity, which in turn involves severe alterations in the regulation of BAT lipogenesis.

Chronic administration of BRL 26830A for 9 weeks improves insulin sensitivity but does not prevent weight gain in gold-thioglucose obese mice.

BRL 26830A, a beta adrenoceptor agonist, has been shown to have antiobesity and antidiabetic properties in rodents. The aim of this study was to study the effects of chronic BRL 26830A treatment (20 mg/kg/day for 9 weeks) on weight gain and the development of insulin resistance in gold-thioglucose-injected mice (GTG). BRL 26830A slowed the rate of weight gain in GTG such that mice weighed significantly less between 2 w and 7 w of treatment. However, at the time of sacrifice (9 w), there was no difference in body weight between treated and untreated GTG. The obesity-induced reduction in lipogenesis in brown adipose tissue (BAT) was increased 9 fold to greater than CON levels. However, weight and fatty acid (FA) content of BAT were reduced, suggesting increased lipid turnover and thermogenesis. Lipogenesis, FA content and fat pad weight were unchanged in white adipose tissue (WAT) and decreased in liver of GTG. Glucose tolerance was improved in both CON and GTG. Hyperglycemia, hyperinsulinemia and changes in cardiac and hepatic glucose oxidation as indicated by PDHC activity were normalized. Serum triglycerides and non-esterified fatty acids were reduced. Thus, chronic BRL 26830A treatment prevented the development of insulin resistance and attenuated weight gain, but did not prevent the development of obesity in this model.

Tissue-specific effect of clofibrate on rat lipogenic enzyme gene expression

Fibrate derivatives are commonly used to treat hyperlipidaemia; however, the mechanism of the antilipidaemic action of these drugs is still unknown. The effect of clofibrate (fibrate derivative) administration for 14 days on lipogenesis and on malic enzyme (EC 1.1.1.40) and fatty acid synthase (EC 2.3.1.85) gene expression in brown and white adipose tissues and in the liver was examined in rats. The rate of brown adipose tissue lipogenesis in the clofibrate-treated animals was significantly lower than that of the control rats. The rate of liver and white adipose tissue lipogenesis was not affected significantly by clofibrate. In brown adipose tissue, the drug treatment resulted in a depression of fatty acid synthase and malic enzyme mRNA levels. The fatty acid synthase mRNA level did not change significantly in the liver, whereas the malic enzyme mRNA level increased approximately 6-fold in this organ after clofibrate treatment. The malic enzyme mRNA level in white adipose tissue increased about 2-fold, while the fatty acid synthase mRNA level was unchanged after clofibrate feeding. The results presented in this paper provide further evidence that the hypolipidaemia caused by treatment of rats with clofibrate cannot be related to the inhibition of fatty acid synthesis in the liver and white adipose tissue. These data also indicate that clofibrate exhibits tissue specificity.

Thyroxine 5'-deiodination mediates norepinephrine-induced lipogenesis in dispersed brown adipocytes.

In euthyroid rats, maximal sympathetic nervous system stimulation (e.g. during cold exposure) results in a 3- to 4-fold increase in brown adipose tissue lipogenesis, a response that is blunted in hypothyroid rats. To further investigate this phenomenon, the role of local type II 5'-deiodinase (5'-DII) was studied in freshly isolated brown adipocytes. In a typical experiment, 1.5 x 10(6) cells were incubated for up to 48 h in a water-saturated 5% CO2-95% O2 atmosphere. After incubation with medium alone or with different concentrations of T4, T3, and/or norepinephrine (NE), lipogenesis was studied by measuring 1) the rate of fatty acid synthesis as reflected by 3H2O incorporation into lipids and 2) the activity of key rate-limiting enzymes, i.e. acetyl coenzyme A carboxylase and malic enzyme, and the results are reported in terms of DNA content per tube. Lipogenesis decreased progressively over time (approximately 40%) when no additions were made to the incubation medium. T4 or T3 partially prevented that inhibition at physiological concentrations (65 x 10[-9] and 0.77 x 10[-9] M, respectively), whereas a receptor-saturating concentration of T3, (154 x 10[-9] M) doubled the lipogenesis rate. The addition of 10(-6) M NE inhibited lipogenesis acutely (approximately 50% by 12 h) and was followed by a progressive stimulation that reached approximately 2-fold by 48 h, but only in the presence of T4. Furthermore, NE did not attenuate T3 (154 x 10[-9] M)-induced lipogenesis. Both the inhibition and the stimulation of lipogenesis caused by NE showed a strong dose-response relationship within the range of 10(-11)-10(-5) M. The role of local 5'-DII was further tested by incubating brown adipocytes with 10(-6) M NE and T4 (65 x 10[-9] M) in the presence of 100 microM iopanoic acid, a potent inhibitor of 5'-DII. Although iopanoic acid did not affect the T3 stimulation of lipogenesis, it did block the approximately 2-fold stimulation of lipogenesis triggered by NE in the presence of T4, confirming the mediation of 5'-DII in this process. In conclusion, lipogenesis in brown adipose tissue is under complex hormonal control, with key roles played by NE, thyroid hormones, and local 5'-DII. As in other tissues, NE-generated signals acutely (12 h) inhibited lipogenesis. However, the presence of the 5'-DII generated enough T3 to stimulate lipogenesis and gradually reverse the short-lived NE-induced inhibition, leading to the 2- to 3-fold response observed at later time points.

CHRONIC ETHANOL CONSUMPTION AMELIORATES THE MATURITY-ONSET DIABETES-OBESITY SYNDROME IN CBA MICE

The effects of a chronic ethanol drinking schedule (20% solution for 6 weeks) on energy balance and carbohydrate and lipid metabolism have been investigated in lean (32-36 g) and obese-diabetic (40-44 g) CBA/Ca mice. The untreated obese-diabetic mice exhibited hyperglycaemia, hypertriglyceridaemia, hyper-insulinaemia and insulin resistance. The chronic ethanol treatment, which yielded plasma ethanol levels of between 1 and 11 mM, lowered the blood glucose, plasma insulin and triacylglycerol levels towards normal in the obese mice, but did not affect these parameters in the lean mice. The body weight of the obese mice tended to return to normal during the 6-week drinking period, although their total energy intake (9.2-10.0 kJ/g/week, food plus ethanol-derived calories) was almost double that of the lean mice (4.8-5.4 kJ/g/week). The blood glucose response to acute insulin injection, which was significantly reduced in the obese mice, became indistinguishable from the response of normal mice after chronic ethanol treatment. Soleus muscle glycogen synthesis in both lean and obese mice was not significantly altered by ethanol drinking, but brown adipose tissue lipogenesis was significantly increased (by 50%) in the obese mice. It is proposed that ethanol is acting chronically to restore insulin sensitivity in the obese diabetic mice at doses which have little or no effect in normal lean animals. This action is exerted, at least in part, at the level of brown adipose tissue lipogenesis.

Effect of adrenalectomy on glucose tolerance and lipid metabolism in gold-thioglucose obese mice

The effect of adrenalectomy (ADX) on body weight, lipogenesis, and glucose tolerance was investigated in mice made obese by a single intraperitoneal injection of gold-thioglucose (GTG). Five weeks after ADX the weight of GTG-obese mice was significantly decreased (GTG-obese+sham-ADX: 39.8 +/- 0.8 g; GTG-obese+ADX: 27.6 +/- 1.1 g; P < 0.05). ADX also reduced serum glucose (GTG-obese+sham-ADX: 16.5 +/- 0.6 mmol/l; GTG-obese+ADX: 10.8 +/- 0.5 mmol/l; P < 0.05) and serum insulin concentrations (GTG-obese+sham-ADX: 197 +/- 36 microU/ml; GTG-obese+ADX: 38 +/- 7 microU/ml; P < 0.05) of fed GTG-obese mice and greatly improved glucose tolerance. ADX lowered liver glycogen content and reduced the fatty acid content of liver, epididymal white adipose tissue (WAT), and interscapular brown adipose tissue (BAT) of fed GTG-obese mice. Lipid synthesis in liver and WAT of GTG-obese mice was decreased by ADX, but lipogenesis in BAT was increased, possibly to provide substrate for increased thermogenesis in this tissue. Effects of ADX on metabolism were not confined to GTG-injected mice, as ADX also reduced body weight and altered the glucose tolerance of age-matched control mice. ADX increased lipid synthesis in liver, WAT, and BAT of fed control mice without an increase in lipid deposition, indicating that there was increased lipid turnover in these lipogenic tissues of ADX mice. ADX reduced the fasting blood glucose concentration of both control and GTG-obese mice to a level below that of sham-ADX control mice (sham-ADX control: 6.0 +/- 0.4 mM; ADX control: 2.9 +/- 0.5 mM; ADX GTG-obese: 3.3 +/- 0.2 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of lipogenesis in rat brown adipose tissue by clofibrate

The effect of clofibrate (Atromid S, ethyl-2-(4-chlorophenoxy)-2-methylpropionate) administration for 7 days to rats on lipogenesis and on some lipogenic enzyme activities in brown adipose tissue (BAT), liver and white adipose tissue (WAT) was examined. As compared to control rats the rate of lipogenesis in BAT in the clofibrate-treated animals was significantly decreased. The rate of liver lipogenesis increased slightly, whereas lipogenesis in the WAT was not affected by clofibrate. In BAT, the drug treatment resulted in depression of fatty acid synthase, ATP-citrate lyase, malic enzyme, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities. The activity of liver fatty acid synthase did not change, ATP-citrate lyase activity slightly decreased, whereas the activity of malic enzyme significantly increased in this organ after clofibrate feeding. The ATP-citrate lyase activity in WAT decreased, while fatty acid synthase and other lipogenic enzymes were not changed after clofibrate feeding. Clofibrate treatment did not influence the activity of NADP-linked isocitrate dehydrogenase and malate dehydrogenase (enzymes not linked directly to lipogenesis), either in BAT, liver or WAT. The data presented suggest that the hypolipidaemic effect of clofibrate in the rat may be due (possibly among other mechanisms) to reduction of the rate of fatty acid synthesis in BAT but not in the liver and WAT.

The development of resistance to the lipogenic effects of insulin in brown and white adipose tissue of spontaneously type II diabetic male CBA/CA mice

1. 1. Lipogenesis in brown adipose tissue and white adipose tissue (WAT) was measured in vivo in spontaneously type II diabetic male CBA/Ca mice. 2. 2. Lipogenic rates rose sharply in brown adipose tissue between the third and fourth month of life, concomitant with the onset of hyperinsulinaemia. However, lipogenic rates fell between the fourth and fifth month of age, and remained low, despite increasing circulating insulin concentrations. 3. 3. Lipogenesis in white adipose tissue showed a modest response to hyperinsulinaemia followed by increasing resistance to elevated insulin concentrations after 5 months of age. 4. 4. Studies involving either the injection of insulin or the intubation of glucose provided further evidence for the development of insulin resistance in both brown and white adipose tissue.

Developmental changes of lipogenic enzyme activities and lipogenesis in brown adipose tissue and liver of the rat

1. 1. Brown adipose tissue (BAT) and liver lipogenesis in vivo estimated by using 3H 2O as tracer was very low and did not change significantly between 10 and 20 days after birth. Lipogenesis increased dramatically in both tissues by weaning at 20 days, peaking between 25 and 30 days of age. Since that time the rate of fatty acid synthesis in BAT decreased gradually to reach adult level after 2 months, whereas in the liver there was a sharp decrease of lipogenesis. 2. 2. The activities of fatty acid synthase, citrate cleavage enzyme, malic enzyme and glucose 6-phosphate dehydrogenase essentially followed a similar course of developmental changes as lipogenesis. 3. 3. In contrast to the enzymes listed above NADP-linked isocitrate dehydrogenase remained unaltered over the period studied, whereas lactate and malate dehydrogenases exhibited very high activity at 10 days after birth and from then decreased to reach adult level at the age of about 20 days. 4. 4. The data obtained indicate that no substantial differences could be detected in the developmental pattern of lipogenesis and lipogenic enzyme activities between BAT and liver up to 30 days of age but after this time these processes were not co-ordinated in both tissues. Beyond this time the BAT was charaterized by a much higher rate of lipogenesis than the liver. 5. 5. The results are discussed in terms of the nutrient changes and the relationship between thermogenesis and lipogenesis in BAT.