Metabolism of very low density lipoproteins in genetically lean or fat lines of chicken

Metabolism of very low density lipoproteins (VLDL) has been compared in fat (FL) and lean (LL) lines of chicken. When refed after fasting, plasma triglyceride concentration reached a significantly higher plateau in FL, although their feed consumption was lower than in LL. Newly synthesized VLDL were studied using anti-lipoprotein lipase antibodies. VLDL triglyceride (TG) concentrations were increased by antibody injection and reached a higher concentration in FL plasma than in LL. Newly synthesized VLDL exhibited a similar lipid composition. Fatty acid profiles were also similar when birds ingested a very low fat diet. Comparison of in vitro affinity of lipoprotein lipase and VLDL from both genotypes did not reveal any difference in Km and Vmax. [14C]labelled VLDL from fat or lean donors were prepared and were injected into chickens from both genotypes. Fractional rate constants did not differ between lines. However, as plasma VLDL-TG pools were very different, plasma turnover was higher in FL than in LL. About 3-fold more VLDL-TG were incorporated in abdominal fat of FL than in LL. Difference in fattening between both genotypes seem to be due to both increased VLDL secretion and VLDL removal from plasma without difference in VLDL characteristics.     

Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects

We previously reported that a eucaloric, low fat, liquid formula diet enriched in simple carbohydrate markedly increased the synthesis of fatty acids in lean volunteers. To examine the diet sensitivity of obese subjects, 7 obese and 12 lean volunteers were given two eucaloric low fat solid food diets enriched in simple sugars for 2 weeks each in a random-order, cross-over design (10% fat, 75% carbohydrate vs. 30% fat, 55% carbohydrate, ratio of sugar to starch 60:40). The fatty acid compositions of both diets were matched to the composition of each subject's adipose tissue and fatty acid synthesis measured by the method of linoleate dilution in plasma VLDL triglyceride. In all subjects, the maximum % de novo synthesized fatty acids in VLDL triglyceride 3;-9 h after the last meal was higher on the 10% versus the 30% fat diet. There was no significant difference between the dietary effects on lean (43+/-13 vs. 12+/-13%) and obese (37+/-15 vs. 6+/-6%) subjects, despite 2-fold elevated levels of insulin and reduced glucagon levels in the obese. Similar results were obtained for de novo palmitate synthesis in VLDL triglyceride measured by mass isotopomer distribution analysis after infusion of [(13)C]acetate. On the 10% fat diet, plasma triglycerides (fasting and 24 h) were increased and correlated with fatty acid synthesis. Triglycerides were higher when fatty acid synthesis was constantly elevated rather than having diurnal variation.Thus, eucaloric, solid food diets which are very low in fat and high in simple sugars markedly stimulate fatty acid synthesis from carbohydrate, and plasma triglycerides increase in proportion to the amount of fatty acid synthesis. However, this dietary effect is not related to body mass index, insulin, or glucagon levels.     

Plasma lipoprotein metabolism in lean and in fat chickens produced by divergent selection for plasma very low density lipoprotein concentration

Plasma lipoprotein metabolism was studied in vivo in two lines of chickens produced by selection for high and low plasma very low density lipoprotein (VLDL) concentration. Rates of VLDL secretion were measured by determining the rate of accumulation of triglyceride in the plasma after intravenous injection of anti-lipoprotein lipase antibody. The clearance of VLDL-triglyceride and its uptake into liver and adipose tissue was examined using radioactively labeled VLDL synthesized in vivo. The rate of VLDL secretion was about threefold higher in the high-VLDL line as compared to the leaner, low VLDL-line (6.7 vs 2.1 mumol VLDL triglyceride/h per ml of plasma). The clearance of VLDL from the circulation of the low VLDL line was much faster than that of the high VLDL line (t1/2 of 3.7 and 13.6 min, respectively). The proportion of administered radiolabel taken up by the abdominal fat pad was substantially greater in the fat line than in the lean line (11.9 vs 4.8%, respectively). Lipoprotein lipase activities in leg muscle and heart were consistently greater in the low-VLDL line and beta-hydroxybutyrate concentrations in the plasma of the low-VLDL line were significantly greater than those in the high-VLDL line (0.86 vs 0.48 mumol/ml). The results show that the approximately tenfold difference in plasma VLDL concentration between lines is primarily due to markedly different rates of hepatic VLDL production and that selection has made a major effect on partitioning of VLDL triglyceride between adipose and other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

The ability of genetically lean or fat slow-growing chickens to synthesize and store lipids is not altered by the dietary energy source

The increasing use of unconventional feedstuffs in chicken’s diets results in the substitution of starch by lipids as the main dietary energy source. To evaluate the responses of genetically fat or lean chickens to these diets, males of two experimental lines divergently selected for abdominal fat content were fed isocaloric, isonitrogenous diets with either high lipid (80 g/kg), high fiber (64 g/kg) contents (HL), or low lipid (20 g/kg), low fiber (21 g/kg) contents (LL) from 22 to 63 days of age. The diet had no effect on growth performance and did not affect body composition evaluated at 63 days of age. Glycolytic and oxidative energy metabolisms in the liver and glycogen storage in liver and Sartorius muscle at 63 days of age were greater in chicken fed LL diet compared with chicken fed HL diet. In Pectoralis major (PM) muscle, energy metabolisms and glycogen content were not different between diets. There were no dietary-associated differences in lipid contents of the liver, muscles and abdominal fat. However, the percentages of saturated (SFA) and monounsaturated fatty acids (MUFA) in tissue lipids were generally higher, whereas percentages of polyunsaturated fatty acids (PUFA) were lower for diet LL than for diet HL. The fat line had a greater feed intake and average daily gain, but gain to feed ratio was lower in that line compared with the lean line. Fat chickens were heavier than lean chickens at 63 days of age. Their carcass fatness was higher and their muscle yield was lower than those of lean chickens. The oxidative enzyme activities in the liver were lower in the fat line than in the lean line, but line did not affect energy metabolism in muscles. The hepatic glycogen content was not different between lines, whereas glycogen content and glycolytic potential were higher in the PM muscle of fat chickens compared with lean chickens. Lipid contents in the liver, muscles and abdominal fat did not differ between lines, but fat chickens stored less MUFA and more PUFA in abdominal fat and muscles than lean chickens. Except for the fatty acid composition of liver and abdominal fat, no interaction between line and diet was observed. In conclusion, the amount of lipids stored in muscles and fatty tissues by lean or fat chickens did not depend on the dietary energy source.     

De novo lipogenesis in the liver and adipose tissues of ducks during early growth stages after hatching

In vivo de novo lipogenesis (DNL) in the liver and adipose tissues of ducks during early developmental stages after hatching has not previously been investigated. In this study, female Peking ducks (Anas platyrhynchos) at weeks 1 to 8 post-hatching were selected for experimentation. We measured the mRNA levels of 6 DNL-related genes in the duck liver, subcutaneous adipose tissue and abdominal adipose tissue by real-time PCR during the 8 weeks. Correlations of the plasma triacylglycerol (TG) and very low density lipoprotein (VLDL) concentrations with fat deposition at these sites were also detected during growth. Our results showed that fat content was highest in the subcutaneous adipose tissue and lowest in the liver during the growth period we studied. Additionally, plasma VLDL and TG were significantly associated with lipid content in adipose tissue (P<0.05), but not in the liver. Lastly, in the growing birds, the expression levels of lipogenic genes (with the exceptions SREBP-1c and SCD1) were much higher in the liver than in the adipose tissues, and the maximal expression levels of these genes occurred at week 4 or 5 at these sites. These findings indicated that the main site of DNL is always the liver in post-hatching ducks, and adipose tissues are of little importance for DNL. Taken together, our results suggested that the plasma lipoproteins contribute greatly to fat deposition in adipose tissues originating from hepatic lipogenesis.     

Anthropometric variables and metabolism in polycystic ovarian disease

Anthropometric, endocrine and metabolic variables, were examined in women with polycystic ovarian syndrome (PCO), and in normal control women. Obese women with PCO had higher plasma insulin values than non obese women with PCO, but lean body mass, glucose tolerance, plasma triglycerides and blood pressure were not different in spite of almost twice the body fat mass in the obese PCO women. However, in comparisons between non-obese PCO and control women, with equal body fat mass, the PCO women had higher blood pressure, plasma triglycerides and insulin, as well as a tendency to increased lean body mass. Both PCO groups had a high waist/hip ratio and larger abdominal fat cells than controls, indicating a preferential abdominal accumulation of adipose tissue. In comparison with abdominal adipocytes, femoral adipocytes were larger and had higher lipoprotein lipase activity in the control women, while in the PCO women these regional differences were not found. Basal and norepinephrine stimulated lipolysis were higher in the abdominal than femoral adipocytes in all groups. Substitution of the PCO women with ethinyl estradiol plus desogestrel during 6 months resulted in a regression of clinical androgenic symptoms as well as a normalization of plasma concentrations of free testosterone and sex hormone binding globulin. However, neither body composition nor metabolism were normalized. It was concluded that body fat distribution is more closely related to hypertension and metabolic derangements than total fat mass in the PCO syndrome. It is suggested that the relative paucity of femoral adipose tissue is due to a lack of specific effects of progesterone on adipocytes in this region.     

Postabsorptive VLDL‐TG Fatty Acid Storage in Adipose Tissue in Lean and Obese Women

Adipose tissue lipoprotein lipase (LPL) is a necessary enzyme for storage of very‐low‐density lipoprotein–triglyceride (VLDL‐TG), but whether it is a rate‐determining step is unknown. To test this hypothesis we included 10 upper‐body obese (UBO), 11 lower‐body obese (LBO), and 8 lean women. We infused ex vivo‐labeled VLDL‐¹⁴C‐TG and then performed adipose tissue biopsies to understand the relationship between VLDL‐TG storage and LPL activity in femoral and upper‐body subcutaneous fat. Both fractional tracer storage and rate of storage of the VLDL‐TG tracer were evaluated. VLDL‐TG storage was also examined as a function of regional adipose tissue blood flow (ATBF), insulin, VLDL‐TG turnover, regional fat mass, fat‐free mass (FFM), and fat cell size. LPL activity per adipocyte was significantly greater in obese than lean women but not significantly different per gram lipid. Both VLDL‐TG fractional tracer storage per kg lipid and VLDL‐TG storage rate per kg lipid were similar in abdominal and femoral fat in all three groups and were not significantly different between groups. Multiple regression analysis identified FFM and femoral fat mass as significant independent predictors of VLDL‐TG fractional tracer storage and insulin as a significant predictor of VLDL‐TG fatty acid storage rate. LPL activity, ATBF, and VLDL‐TG turnover did not predict VLDL‐TG storage. We conclude that lower FFM and greater plasma insulin are associated with greater VLDL‐TG deposition in abdominal subcutaneous and femoral fat. Greater femoral fat mass signals greater femoral VLDL‐TG storage. We suggest that the differences in VLDL‐TG storage in abdominal and femoral fat that occur with progressive obesity are regulated through mechanisms other than LPL activity.     

Lipoprotein secretion in lean and obese Zucker female rats in vivo and in a single-pass-perfused liver preparation

The plasma lipoprotein composition as well as lipoprotein synthesis and secretion were studied in vivo and in a single-pass-perfused liver preparation in lean and obese Zucker rats. Compared with their lean littermates the levels in the plasma of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) + low density lipoprotein (LDL) and high density lipoprotein (HDL) were increased 4-, 2- and 2.5 fold, respectively, in obese rats. In these rats both VLDL and IDL + LDL were enriched in triglycerides, while the HDL were enriched in cholesterol. Although the VLDL and IDL + LDL protein concentrations were the same in lean and obese rats, the HDL protein concentration was 3-fold greater in the obese rats. Both the lean and obese rats incorporated similar amounts of [14C]leucine into total liver protein. However, obese rats incorporated 2.5-fold and 6-fold more [14C]leucine into VLDL and HDL in vivo, 2.7-fold and 1.7 fold more [35S]methionine in VLDL and HDL present in the perfusate, than did lean rats. The perfusate [35S]S-labelled apoproteins (apo-B100, B48; apo-E, apo-AI, apo-AIV and apo-C) were separated by gel electrophoresis and identified by autoradiography. Incorporation of [3H]glycerol into liver, VLDL, IDL + LDL and HDL triglycerides was 2-, 48-, 13- and 1.5-fold higher in obese than in lean rats, respectively. The [3H]-labelled triglycerides in VLDL and IDL + LDL present in the perfusate was 5.4-fold and 4.4-fold more in obese rat. There was no difference in the incorporation of [3H]glycerol into triglycerides of perfusate HDL between the two genotypes of rats. Thus, the hypertriglyceridaemia observed in obese Zucker rats results from very high synthetic rates of both the lipid and protein moieties of plasma lipoproteins. Before this study, no report of the simultaneous triglycerides and protein synthesis in vivo and in a single-pass-perfused liver preparations had been reported.     

Studies on the mechanism of hypertriglyceridemia in the genetically obese Zucker rat

The possibility that impaired removal of lipoprotein triglyceride from the circulation may be a participating factor in the hypertriglyceridemia of the obese Zucker rat was examined. We found no significant differences in the heparin-released lipoprotein lipase (LPL) activities of the adipose tissue, skeletal muscle, and heart (expressed per gram of tissue) from the lean and obese Zucker rats. Furthermore, the kinetic properties of adipose tissue and heart LPL from the lean and obese rats were similar, indicating that the catalytic efficiency of the enzyme was unaltered in the obese animals. The postheparin plasma LPL activities of lean and obese rats were also similar. However, the postheparin plasma hepatic triglyceride lipase (H-TGL) activity in the obese rats was elevated. The higher activity of H-TGL could not alleviate the hypertriglyceridemia in these animals. Since hypertriglyceridemia in the obese rats could also be due to the hepatic production of triglyceride-rich lipoproteins which are resistant to lipolysis, we therefore isolated very low density lipoproteins (VLDL) from lean and obese rat liver perfusates and examined their degradation by highly purified human milk LPL. Although certain differences were observed in hepatic VLDL triglyceride fatty acid composition, the kinetic patterns of LPL-catalyzed triglyceride disappearance from lean and obese rat liver perfusate VLDL were similar. The isolated liver perfusate VLDL contained sufficient apolipoprotein C-II for maximum lipolysis. These results indicate that impaired lipolysis is not a contributing factor in the genesis of hypertriglyceridemia in the genetically obese Zucker rat. The hyperlipemic state may be attributed to hypersecretion of hepatic VLDL and consequent saturation of the lipolytic removal of triglyceride-rich lipoproteins from the circulation.     

Letting lipids go: hormone-sensitive lipase

PURPOSE OF REVIEW: Despite their pathophysiological importance, the molecular mechanisms and enzymatic components of lipid mobilization from intracellular storage compartments are insufficiently understood. The aim of this review is to evaluate the role of hormone-sensitive lipase in this process. RECENT FINDINGS: Hormone-sensitive lipase exhibits a broad specificity for lipid substrates such as triglycerides, diglycerides, cholesteryl esters, and retinyl esters and the enzyme is in a wide variety of tissues. The high enzyme activity in adipose tissue was considered rate-limiting in the degradation of stored triglycerides. This view of a single enzyme controlling the catabolism of stored fat was challenged by recent findings that in hormone-sensitive lipase deficient mice adipose tissue triglycerides were still hydrolyzed and that these animals were leaner than normal mice. These results indicated that in adipose tissue hormone-sensitive lipase cooperates with other yet unidentified lipases to control the mobilization of fatty acids from cellular depots and that this process is coordinately regulated with lipid synthesis. Induced mutant mouse lines that overexpress or lack hormone-sensitive lipase also provided evidence that hormone-sensitive lipase-mediated cholesteryl ester hydrolysis is involved in steroid-hormone production in adrenals and affects testis function. Finally, hormone-sensitive lipase deficiency in mice results in a lipoprotein profile characterized by low triglyceride and VLDL levels and increased HDL cholesterol concentrations. SUMMARY: The 'anti-atherosclerotic' plasma lipoprotein profile and the fact that hormone-sensitive lipase deficient animals become lean identifies the inhibition of hormone-sensitive lipase as a potential target for the treatment of lipid disorders and obesity.     

Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice

The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity.     

Epistatic effect between ACACA and FABP2 gene on abdominal fat traits in broilers

Epistasis is generally defined as the interaction between two or more genes or their mRNA or protein products to influence a single trait. Experimental evidence suggested that epistasis could be important in the determination of the genetic architecture of complex traits in domestic animals. Acetyl-coenzyme A carboxylase alpha (ACACA) and fatty acid binding protein 2 (FABP2) are both key factors of lipogenesis and transport. They may play a crucial role in the weight variability of abdominal adipose tissue in the growing chicken. In this study, the polymorphisms of c.2292GA in ACACA and c.-561AC in FABP2 were detected among individuals from two broiler lines which were divergently selected for abdominal fat content. Epistasis between the two SNPs on abdominal fat weight (AFW) and abdominal fat percentage (AFP) was analyzed. The additive × additive epistatic components between these two SNPs were found significant or suggestively significant on both AFW and AFP in lean lines of the 9th and 10th generation; whereas, it was not significantly associated with either AFW or AFP in fat lines. At the same time, there were not any other significant epistatic components found in both generations or in both lines. Significant epistatic effects between these two SNPs found only in the lean lines could partly be due to the fact that the abdominal fat traits in these two experimental lines have been greatly modified by strong artificial selection. The results suggested that the epistasis mode may be different between the lean and fat chicken lines. Our results could be helpful in further understanding the genetic interaction between candidate genes contributing to phenotypic variation of abdominal fat content in broilers.     

Metabolism in two breeds of geese with moderate or large overfeeding induced liver-steatosis

Biochemical mechanisms which may control fat deposition in liver and/or peripheral tissues have been studied in Poland and Landes geese. Post-prandial plasma substrates and post-heparin lipoprotein-lipase (LPL) activity were measured in 10-week-old animals. At 23 weeks of age, geese were overfed for 14 days then slaughtered. Hepatic steatosis was more important in Landes geese, while muscle and subcutaneous adipose tissue were less developed. In this breed, fatty liver weight negatively scaled to LPL activity, suggesting that a low LPL activity is a limiting factor of peripheral fat deposition. Consequently, non-catabolized VLDL may return to liver and increase hepatic steatosis. In Poland geese, such a mechanism does not exist. On the other hand, fatty liver weight was positively correlated to very low density lipoproteins (VLDL) and triacylglycerols measured in overfed Poland geese, suggesting that lipids synthetized by liver are better transferred from liver to extrahepatic tissues. Kinetics of post-prandial plasma glucose, triacylglycerols, phospholipids and uric acid were similar in the two breeds. However, the marked decrease in post-prandial plasma glycerol in Poland geese suggests that an extrahepatic tissue lipolysis inhibition could contribute to the higher peripheral fattening in overfed Poland geese and could be a limiting factor of hepatic steatosis in this breed.     

Microarray analysis of genes differentially expressed in the liver of lean and fat chickens

Excessive accumulation of lipids in the adipose tissue is one of the main problems faced by the broiler industry nowadays. In chicken, lipogenesis occurs essentially in the liver, in which much of the triglycerides that accumulate in avian adipose tissue are synthesized. In order to better understand the gene expression and its regulation in chicken liver, the gene expression profiles of liver at developmental stages of chicken (1 week, 4 weeks and 7 weeks of age) were investigated and differentially expressed genes between lean and fat chicken lines divergently selected for abdominal fat content for eight generations were screened. Our data indicated that 4 weeks of age was a very important stage on chicken liver lipogenesis compared to 1 week and 7 weeks of age, and the glycometabolism in chicken liver could be related to lipid metabolism and the difference of glycometabolism could be another potential reason for the fat and lean phenotype occurrence besides the difference of lipogenesis in chicken liver. Our result have established groundwork for further study of the basic genetic control of chicken obesity and will benefit chicken research communities as well as researches that use chicken as a model organism for developmental biology and human therapeutics.     

Why are young broiler chickens fatter than layer-strain chicks?

1. The abdominal fat pads of 5 week-old broiler and layer chicks incorporated 6.0 and 3.9% of intravenously-injected 14C-labelled very low density lipoproteins respectively. 2. These proportions of total plasma lipoprotein flux were sufficient to account for about 65-70% of the rate of fat deposition in broilers, but were more than 4-fold greater than that the rate of fat deposition in layers. 3. [14C]Palmitate taken up into adipose tissue of layer chicks had a t1/2 of 2-3 days. 4. There was no significant turnover of adipose tissue triglycerides in broilers and this appears to be a major reason for their relative fatness.     

Characterization of the plasma lipoproteins of the genetically obese hyperlipoproteinemic Zucker fatty rat

The plasma lipoproteins of the Zucker fatty rat were characterized with respect to lipid and apoprotein composition, and results were compared with those obtained from lean controls. Information on apoproteins was obtained from gel filtration experiments and electrophoresis on polyacrylamide gels. Very low density lipoproteins (VLDL) were increased several-fold in fatties, and 78% of their mass was triglycerides compared with 60% in the controls. Low density (LDL) and high density (HDL) lipoproteins were increased by a factor of 2, although their compositions were similar to those of the controls. Levels of apoVLDL, apoLDL, and apoHDL were five, two and two times higher, respectively, in the fatties, and the two most rapidly moving subunit peptides on polyacrylamide gels were disproportionately elevated in the apoproteins. The slower of these two bands was present in relatively greater amounts than the faster one in fatties. If the slower peptide is an activator of lipoprotein lipase, analogous to the comparable subunit peptides of human apolipoproteins, plasmas of fatties could contain up to 10 times more lipase activator activity than control plasma. This finding, and the fact that adipose tissue lipoprotein lipase activity of fatties was about 150% of controls, suggests that fatties have increased capacities for VLDL catabolism. We have previously shown that hepatic VLDL secretory rates are higher than normal in these animals. The increased capacity for catabolism may be a response to the altered secretory rates.     

Effect of high-carbohydrate feeding on triglyceride and saturated fatty acid synthesis

It has been known for decades that low-fat, high-carbohydrate diets can increase plasma triglyceride levels, but the mechanism for this effect has been uncertain. Recently, new isotopic and nonisotopic methods have been used to determine in vivo whether low-fat, high-carbohydrate diets increase triglyceride levels by stimulating fatty acid synthesis. The results of a series of studies in lean and obese weight-stable volunteers showed that very-low-fat (10%), high-carbohydrate diets enriched in simple sugars increased the fraction of newly synthesized fatty acids, along with a proportionate increase in the concentration of plasma triglyceride. Furthermore, the concentration of the saturated fatty acid, palmitate, increased and the concentration of the essential polyunsaturated fatty acid, linoleate, decreased in triglyceride and VLDL triglyceride. The magnitude of the increase in triglyceride varied considerably among subjects, was unrelated to sex, body mass index, or insulin levels, and was higher when fatty acid synthesis was constantly elevated rather than having a diurnal variation. It was notable that minimal stimulation of fatty acid synthesis occurred with higher fat diets (>30%) or with 10% fat diets enriched in complex carbohydrate. Public health recommendations to reduce dietary fat must take into account the distinct effects of different types of carbohydrate that may increase plasma triglycerides and fatty acid synthesis in a highly variable manner. The mediators and health consequences of this dietary effect deserve further study.     

The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity

Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor gamma angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.