Lipid Storage In Adipose Tissue Research Articles

Inactivation of the C. elegans lipin homolog leads to ER disorganization and to defects in the breakdown and reassembly of the nuclear envelope

The nuclear envelope (NE) is a dynamic structure, undergoing periods of growth, breakdown and reassembly during the cell cycle. In yeast, altering lipid synthesis by inactivating the yeast homolog of lipin, a phosphatidic acid phosphohydrolase, leads to disorganization of the peripheral ER and abnormal nuclear shape. These results suggest that lipid metabolism contributes to NE dynamics; however, since yeast undergo closed mitosis, the relevance of these observations to higher eukaryotes is unclear. In mammals, lipin has been implicated in adipose tissue differentiation, insulin resistance, lipid storage and obesity, but the underlying cellular defects caused by altering lipin levels are not known. Here, we identify the Caenorhabditis elegans lipin homolog (LPIN-1) and examine its affect on NE dynamics. We find that downregulating LPIN-1 by RNAi results in the appearance of membrane sheets and other abnormal structures in the peripheral ER. Moreover, lpin-1 RNAi causes defects in NE breakdown, abnormal chromosome segregation and irregular nuclear morphology. These results uncover cellular processes affected by lipin in metazoa, and suggest that lipid synthesis has a role in NE dynamics.

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

The Lou/C rat: a model of spontaneous food restriction associated with improved insulin sensitivity and decreased lipid storage in adipose tissue

The inbred Lou/C rat, originating from the Wistar strain, has been described as a model of resistance to diet-induced obesity, but little is known about its metabolism. Since this knowledge could provide some clues about the etiology of obesity/insulin resistance, this study aimed at characterizing glucose and lipid metabolism in Lou/C vs. Wistar rats. This was achieved by performing glucose and insulin tolerance tests, euglycemic hyperinsulinemic clamps, and characterization of intracellular insulin signaling in skeletal muscle. Substrate-induced insulin secretion was evaluated using perfused pancreas and isolated islets. Finally, body fat composition and the expression of various factors involved in lipid metabolism were determined. Body weight and caloric intake were lower in Lou/C than in Wistar rats, whereas food efficiency was similar. Improved glucose tolerance of Lou/C rats was not related to increased insulin output but was related to improved insulin sensitivity/responsiveness in the liver and in skeletal muscles. In the latter tissue, this was accompanied by improved insulin signaling, as suggested by higher activation of the insulin receptor and of the Akt/protein kinase B pathway. Fat deposition was markedly lower in Lou/C than in Wistar rats, especially in visceral adipose tissue. In the inguinal adipose depot, expression of uncoupling protein-1 was detected in Lou/C but not in Wistar rats, in keeping with a higher expression of peroxisome proliferator-activated receptor-gamma coactivator-1 in these animals. The Lou/C rat is a valuable model of spontaneous food restriction with associated improved insulin sensitivity. Independently from its reduced caloric intake, it also exhibits a preferential channeling of nutrients toward utilization rather than storage.

Purified chickpea or lentil proteins impair VLDL metabolism and lipoprotein lipase activity in epididymal fat, but not in muscle, compared to casein, in growing rats

It is well known that the legume proteins have a lowering effect on plasma cholesterol and triacylglycerols (TG) concentrations compared to animal proteins. The protein itself, as well as non-protein constituents, naturally present in legumes may be implicated. The effects of various dietary purified legumes proteins compared to casein, were determined on plasma TG level, VLDL concentration and composition. Moreover, lipoprotein lipase (LPL) activity in epididymal fat, gastrocnemius and heart was investigated to evaluate in these tissues their capacity to release free fatty acids from their TG substrate and the liver capacity to stock the TG. Weaning male Wistar rats were fed ad libitum one of the following diets: 200 g/kg diet of purified proteins of lentil (L), or chickpea (CP) or casein (CAS). At day 28, VLDL were isolated from plasma sample by a single ultracentrifugation flotation. Hepatic lipase and LPL activity in epididymal fat, gastrocnemius and heart were measured by using glycerol tri [9-10(n)-(3)H] oleate emulsion as substrate. Compared with CAS diet, the CP and L protein diets exhibited similar cholesterolemia, but lower triglyceridemia (1.9-fold and 2.5-fold) and VLDL particle number, as measured by their reduced contents of TG and apolipoproteins. CP and L protein diets reduced liver TG and cholesterol by 31 and 45%, respectively compared to CAS diet. Furthermore, LPL activity in adipose tissue of rats fed CP or L was 1.6-fold lower than that of rats fed CAS. There was no significant difference in heart and gastrocnemius LPL activities with the three proteins. In contrast, hepatic lipase activity was higher in rats fed CP and L diets. The low food efficiency ratio of purified CP and L proteins related to CAS is associated with decreased plasma VLDL and adipose tissue LPL activity. The low liver TG concomitant with reduced TG and apolipoproteins contents of VLDL confirm that hypotriglyceridemia is essentially due to impaired synthesis, exportation and transport of TG by VLDL which prevent lipid storage in adipose tissue.

Metabolic flexibility and insulin resistance

Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this "metabolic inflexibility" is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate (amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high-fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics.

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

The beneficial metabolic actions of peroxisome proliferator-activated receptor gamma (PPARgamma) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This study aimed to assess the contribution of GC attenuation to PPARgamma agonism action on gene expression in visceral adipose tissue and global metabolic profile. Rats were treated (2 weeks) with the PPARgamma agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARgamma-mediated GC attenuation. mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. Whereas HiCORT did not alter RWAT mass, RSG increased the latter (+33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPARgamma agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORT-induced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. The GC and PPARgamma pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPARgamma agonism are retained under imposed high ambient GC, and are therefore independent from PPARgamma effects on 11beta-HSD1-mediated GC production.

In Vivo Evidence for a Role of Adipose Tissue SR-BI in the Nutritional and Hormonal Regulation of Adiposity and Cholesterol Homeostasis

This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.

Lipin: a determinant of adiposity, insulin sensitivity and energy balance

Lipodystrophy and obesity represent extreme ends of the adiposity spectrum, and both are associated with conditions such as insulin resistance, diabetes and atherosclerosis. This points to a key role for adipose tissue in metabolic homeostasis and has spurred efforts to identify genes involved in adipose tissue development and function. Lipin is one such gene. Variations in lipin expression levels in mouse models produce wide variations in adiposity ranging from lipodystrophy in lipin-deficient mice, to obesity in mice with enhanced lipin expression in either adipose tissue or muscle. These effects reflect important roles for lipin in key metabolic processes including cell differentiation and lipid storage in adipose tissue, and energy utilization in muscle. This review summarizes the work to date on lipin, focusing on its effects on adipose tissue mass and energy balance, insulin sensitivity and cellular function.

Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial

Background Several clinical studies have demonstrated that body weight increases after treatment with thiazolidinediones (TZDs). Prior studies have demonstrated an increase in insulin-stimulated lipid storage in adipose tissue. Some, but not all, studies demonstrate reductions in visceral adipose tissue. Changes in body weight are the result of changes in energy intake, energy expenditure, or both. Objectives Based on these findings, the primary aim of this study was to evaluate the effect of TZDs on visceral, subcutaneous, and total body fat. Secondary aims were to determine the effects of pioglitazone on ( a) energy expenditure, ( b) hunger and satiety, ( c) blood lipids, and ( d) the role of insulinemia/sulfonylurea usage on weight gain in patients with type 2 diabetes. Subjects and Methods We performed a randomized, double-blind, placebo-controlled trial in 48 men and women with type 2 diabetes who had not previously received treatment with TZDs. Patients were treated for 24 weeks with 45 mg/d of pioglitazone or a matching placebo. Body composition was measured by dual-energy x-ray absorptiometry. Visceral and subcutaneous fat were measured by computed tomography. Resting metabolic rate and thermogenic response to a test meal were measured by indirect calorimetry before and after a standardized meal. Hunger and satiety were measured with visual analog scales before and after the same test meal. Blood was collected for the measurement of fasting glucose and insulin levels, hemoglobin A 1c levels, and lipid content. Results Pioglitazone treatment resulted in a decrease in hemoglobin A 1c level by 0.96 ± 1.1% vs 0.11 ± 0.8% in the placebo group ( P < .005). Body weight and fat increased steadily in the patients treated with pioglitazone during the 6 months of the study (+3.9 ± 3.1 kg at 6 months in pioglitazone-treated patients vs −0.8 ± 3.4 kg in the placebo-treated patients). Subcutaneous fat in the trunk, arms, and legs were all increased in the pioglitazone-treated group. Visceral fat did not change significantly in either group. Neither resting metabolic rate nor the thermogenic responses to a meal were altered by pioglitazone. Subjective measures of hunger (visual analog scale) did not change with pioglitazone treatment. Triglycerides fell in the pioglitazone-treated group (−58.5 ± 124 mg/dL, P < .003). Neither the prior use of sulfonylureas nor the level of insulinemia before treatment was a predictor of weight or fat change. Conclusion Pioglitazone increased subcutaneous body fat, but not visceral fat. There was no measurable effect on energy expenditure or hunger/satiety. In contrast to the placebo-treated patient with diabetes, weight gain occurs in the face of falling hemoglobin A 1c and triglyceride levels.

Lipid Metabolism and Nutrient Partitioning Strategies

The increasing prevalence of overweight and obesity worldwide is daunting and requires prompt attention by the affected, health care profession, government and the pharmaceutical industry. Because overweight/obesity are defined as an excess of adipose tissue mass, all approaches in prevention and treatment must consider redirecting lipid storage in adipose tissue to oxidative metabolism. Lipid partitioning is a complex process that involves interaction between fat and other macronutrients, particularly carbohydrate. In an isocaloric environment, when fat is stored carbohydrate is oxidized and vice versa. Processes that influence fat partitioning in a manner in which weight is maintained must be modified by changes in organ-specific fat transport and metabolism. When therapy is considered, however, changes in lipid partitioning alone will be ineffective unless a negative energy balance is also achieved, i.e. energy expenditure exceeds energy intake. The intent of this review is to focus on molecules including hormones, enzymes, cytokines, membrane transport proteins, and transcription factors directly involved in fat trafficking and partitioning that could be potential drug targets. Some examples of favorably altering body composition by systemic and/or tissue specific modification of these molecules have already been provided with gene knockout and/or transgenic approaches in mice. The translation of this science to humans remains a challenging task.

Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit.

AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor that regulates glucose and lipid metabolism by phosphorylating key regulatory enzymes. Despite the major role of adipose tissue in regulating energy partitioning in the organism, the role of AMPK in this tissue has not been addressed. In the present study, we subjected AMPKalpha2 knockout (KO) mice to a high-fat diet to examine the effect of AMPK on adipose tissue formation. Compared with the wild type, AMPKalpha2 KO mice exhibited increased body weight and fat mass. The increase in adipose tissue mass was due to the enlargement of the preexisting adipocytes with increased lipid accumulation. However, we did not observe any changes in adipocyte marker expression, such as peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and adipocyte fatty acid-binding protein (aFABP/aP2), or total cell number. Unlike impaired glucose homeostasis observed on normal diet feeding, when fed a high-fat diet AMPKalpha2 KO mice did not show differences in glucose tolerance and insulin sensitivity compared with wild-type mice. Our results suggest that the increase in lipid storage in adipose tissue in AMPKalpha2 KO mice may have protected these mice from further impairment of glucose homeostasis that normally accompanies high-fat feeding. Our study also demonstrates that lack of AMPKalpha2 subunit may be a factor contributing to the development of obesity.

Leptin and the control of respiratory gene expression in muscle.

Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity. In this study, we examined the direct and indirect effects of leptin signaling on mitochondrial enzymes including those essential for peripheral fatty acid oxidation. We assessed the impact of leptin using the JCR:LA-cp rat, which lacks functional leptin receptors. The activities of marker mitochondrial enzymes citrate synthase (CS) and cytochrome oxidase (COX) were similar between wild-type (+/?) and corpulent (cp/cp) rats. In contrast, several tissues showed variations in the fatty acid oxidizing enzymes carnitine palmitoyltransferase II (CPT II), long-chain acyl-CoA dehydrogenase (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (HOAD). It was not clear if these changes were due to loss of leptin signaling or to insulin insensitivity. Consequently, we examined the effects of leptin on cultured C(2)C(12) and Sol8 cells. Leptin (3 days at 0, 0.2, or 2.0 nM) had no direct effect on the activities of CS, COX, or fatty acid oxidizing enzymes. Leptin treatment did not affect luciferase-based reporter genes under the control of transcription factors involved in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), nuclear respiratory factor-2 (NRF-2)) or fatty acid enzyme expression (peroxisome proliferator-activated receptors (PPARs)). These studies suggest that leptin exerts only indirect effects on mitochondrial gene expression in muscle, possibly arising from insulin resistance.

Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion.

To assess the importance of the sympathetic nervous system in regulating body weight during prolonged leptin infusion, we evaluated food intake, body weight, and physical activity in conscious, unrestrained rats. Initial studies illustrated that prolonged intracerebroventricular (ICV) infusion of leptin enhanced substrate oxidation so that adipose tissue lipid stores were completely ablated, and muscle triglyceride and liver glycogen stores were depleted. After neonatal chemical sympathectomy, changes in weight and food intake were compared in groups of sympathectomized (SYM) and control (CON) adult animals during ICV infusion of leptin. CON animals lost 60 +/- 9 g over 10 days vs. 25 +/- 3 g in the SYM animals when food intake was matched between the two groups. Greater weight loss despite similar energy intake points to an important role of the sympathetic nervous system in stimulating energy expenditure during ICV leptin infusion by increasing the resting metabolic rate, since no differences in physical activity were observed between CON and SYM groups. In conclusion, activation of the SNS by leptin increases energy expenditure by augmenting the resting metabolic rate.

Sex differences in lipid metabolism during reproduction in free-living tree lizards ( Urosaurus ornatus)

Understanding the relationship between energy metabolism and signals that regulate reproduction may provide insight into the coordination of the energetically costly behavioral and physiological events that occur during reproduction. Significant changes in the utilization of stored lipids may occur during reproduction and the patterns of utilization observed often differ between females and males. Changes in levels of stored lipid reserves have been described extensively in animals from many taxa, but detailed biochemical analyses of alterations in the enzymes and substrates regulating lipid metabolism during periods of active reproductive effort rarely have been performed. In addition, few studies have compared males and females from the same population during the same reproductive season. In this study we examined lipid metabolism in free-living female and male tree lizards across a single reproductive season. We measured lipid stores, circulating lipid substrates, and the activities of enzymes regulating lipid storage and release in both liver and adipose tissue. Overall, females and males showed significant variation in abdominal fat body mass, liver total lipid, the activity of an enzyme regulating fat storage (DGAT) in both of these tissues, and circulating free fatty acids across the reproductive season. In females, total fat body mass, adipose DGAT, liver lipid, and liver DGAT significantly varied across reproductive stage, with vitellogenic and Gravid females often at opposite extremes. In males, fat body mass and liver fat varied across reproductive stage (without significant variation in DGAT in either tissue), as did circulating glycerol and free fatty acids. Correlations among sex steroid hormone levels and lipid metabolism variables suggested a role for these hormones in producing the patterns observed in each sex and in the observed sex differences lipid metabolism.

Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families

The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses ( P=0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling–sibling correlation for the HSL trait (0.51, P<0.01 ). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.

Low-protein diet prevents tissue lipoprotein lipase activity increase in growing rats.

The time course of changes in tissue lipolytic activities was studied in young rats during the consumption of a low-protein diet containing 50 g protein/kg (40 g wheat gluten +10 g casein/kg) for 28 d followed by balanced refeeding with 200 g protein/kg (160 g wheat gluten +40 g casein/kg) for 28 d. Lipoprotein lipase (LPL) activities were compared with the values of a control group fed a balanced diet containing 200 g protein/kg for 56 d. At the end of protein malnutrition period, the epididymal fat tissue LPL activity represented 36 %, and that of heart and gastrocnemius was 44 %, of those of the control group. These differences were accompanied by lower serum- and VLDL-triacylglycerols (TAG), respectively 47.6 % and 31 % of the control group values, probably resulting from reduced synthesis of VLDL-apolipoproteins (29 % of control group values), concomitant with liver lipid accumulation (4.8-fold) and little lipid storage in epididymal fat tissue. At day 2 of refeeding, there was no significant difference in liver and epididymal fat tissue LPL activities between experimental and control rats. At the end of the refeeding period, LPL activity of epididymal fat and liver lipolytic activity had increased and became similar to control group values. The consumption of a low-protein diet prevented the increase in extrahepatic LPL activities as observed in the control group. The alterations in LPL activity suggest that a low-protein diet limits lipid storage in adipose tissue due to reduced serum VLDL-TAG availability.

Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue.

Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity of adipocytes from inbred mouse strains resistant or sensitive to diet-induced obesity

We evaluated insulin sensitivity in epididymal adipocytes from two mouse strains shown to be either sensitive (AKR/J, n = 14) or resistant (SWR/J, n = 12) to the development of obesity when fed a high-fat diet. Half of each strain was fed a chow (CH) diet (12% fat), and half received a sweetened condensed milk (CM) diet (33% fat). After 1 wk, epididymal adipose depots were removed and digested with collagenase, and glucose transport was measured with labeled 2-deoxyglucose. Plasma glucose and insulin were slightly higher in AKR/J than SWR/J mice (glucose: 139.7 vs. 118.8 mg/dl, P < 0.06; insulin: 3.45 vs. 2.99 ng/ml, P < 0.04). One week of high-fat feeding increased adipose depot mass and carcass lipid in both strains to approximately the same extent. Adipocytes from AKR/J mice had greater insulin-stimulated glucose transport compared with SWR/J mice at both submaximal and maximal insulin levels (P < 0.0001). Short-term feeding of the high-fat diet increased AKR/J adipocyte insulin sensitivity but decreased the sensitivity of SWR/J adipocytes to insulin. The differences in adipocyte insulin sensitivity between strains were not explained by differences in adipocyte cell size. Access to the high-fat CM diet for 12 wk increased total dissected adipose depot size by 209% in the AKR/J mice and 82% in the SWR/J mice. These data clearly demonstrate that the two strains differ in adipocyte insulin sensitivity as well as sensitivity to dietary obesity. Increased adipocyte insulin sensitivity could contribute to a predisposition to increase adipose tissue lipid stores with diets high in fat content.

Evolution de la capacité d'estérification des acides gras dans les adipocytes de rat avant le sevrage : effet de la suralimentation lactée

During the suckling period, lipid storage in rat adipose tissue arises from exogenous triglycerides, as milk contains a large amount of lipid. In the present work, we studied the effect of overfeeding during the suckling period on the developmental pattern of the fatty acid esterification pathway in fat cells. Early overfeeding was induced by restricting litter size; at 2 days of age, the pups were randomly distributed to form litters of 4 (overfed group) or 8 (controls). During the suckling period the activity of lipoprotein lipase (LPL), glycerophosphate dehydrogenase (G3PDH), glycerophosphate acyl transferase (GPAT) and acyl CoA ligase were measured in isolated fat cells from the inguinal adipose tissue. As early as 10 days of age, plasma triglyceride levels were increased in overfed pups as compared to the controls and, in these animals, the adipose tissue was overdeveloped, mainly due to fat cell hypertrophy. At that age, overfeeding induced a significant increase in LPL and GPAT activities, but acyl CoA ligase and GPDH were not modified in overfed pups. Fat cell hypertrophy appeared to be responsible for the increased GPAT activity in the overfed pups. On the contrary, the effect of overfeeding on LPL activity was not only related to fat cell enlargement, as the enzyme activity continued to increase in the overfed rats when expressed per unit of cell surface area. These results show that overfeeding during the suckling period rapidly induced an increase in the fat storage capacity of the adipose tissue. This suggests that circulating triglyceride levels could regulate directly or through hormonal control the activity of the fatty acid esterification pathway in fat cells.