Biomedical subjects

Katherine Cianflone

Publications and source records attributed to Katherine Cianflone.

32 records · Page 2Linked to original sources

PubMed2004

Addition of glucose to an oral fat load reduces postprandial free fatty acids and prevents the postprandial increase in complement component 3.

BACKGROUND: Elevated fasting plasma concentrations of complement component 3 (C3) are associated with elevated fasting and postprandial triacylglycerol concentrations, insulin resistance, obesity, and coronary artery disease. C3 is the central component of the complement system and the precursor of acylation-stimulating protein (ASP). Insulin and ASP are principal determinants of free fatty acid (FFA) trapping by adipose tissue. OBJECTIVE: Because controversy exists concerning postprandial changes in C3 and because meal composition may influence complement activation, we studied postprandial lipemia in relation to changes in plasma C3. DESIGN: After an overnight fast, 6 healthy men ( +/- SD age: 23 +/- 2 y) underwent 4 oral liquid challenges: fat (50 g/m(2) body surface), glucose (37.5 g/m(2)), fat and glucose (mixed test), and water (as a control test) in a random, crossover design. RESULTS: Plasma ASP concentrations did not change postprandially in any test. Changes in C3 concentration were observed only after the fat challenge: elevated concentrations occurred between 1 and 3 h, and a maximum increase of 11% occurred at 2 h (P = 0.05). Postprandial triacylglycerolemia did not differ significantly between the fat and mixed tests. The FFA response after the fat challenge was the highest of all the tests (P < 0.05 for all comparisons) and was accompanied by an increase in ketone bodies (maximum at 6 h); this increase did not occur after the mixed test, which suggests less hepatic FFA delivery. CONCLUSIONS: When glucose is added to an oral fat load, the postprandial FFA response is reduced, and the fat-specific increase in C3 is prevented. After ingestion of fat without glucose, the lack of insulin response may lead to C3-mediated peripheral FFA trapping, which probably serves as a backup system in case of insufficient or inefficient insulin-dependent FFA trapping.

Adult↗

PubMed2004

Regulation of fatty acid transport.

PURPOSE OF REVIEW: The aim of the present review is to summarize recent developments in the area of regulation of fatty acid transport. RECENT FINDINGS: While controversy still exists regarding the contribution of passive diffusion versus protein-mediated fatty acid transport, both processes are now widely accepted. With the recent identification of an increasing number of putative fatty acid transporters, emphasis has been placed on regulation including fatty acid transport function of the protein, and also possible associated functions (acylCoA synthase activity and vectorial channelling to intracellular processing). Deciphering these issues has been facilitated through the use of loss-of-function (such as knockout) and gain-of-function (cell transfectants and transgenic mice) models. SUMMARY: It is likely that our concept of fatty acid transport will continue to converge, incorporating the individual functions of the wide variety of fatty acid transporters into an integrated physiologic framework with relevance to a number of diseases.

Animals↗

PubMed2004

Diabetes, lipids, and adipocyte secretagogues.

That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.

Adipose Tissue↗

PubMed2004

Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP.

Acylation-stimulating protein (ASP) is a lipogenic hormone secreted by white adipose tissue (WAT). Male C3 knockout (KO; C3(-/-)) ASP-deficient mice have delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The objective of this study was to examine the mechanism(s) by which ASP deficiency induces differences in postprandial TG clearance and body composition in male KO mice. Except for increased (3)H-labeled nonesterified fatty acid (NEFA) trapping in brown adipose tissue (BAT) of KO mice (P = 0.02), there were no intrinsic tissue differences between wild-type (WT) and KO mice in (3)H-NEFA or [(14)C]glucose oxidation, TG synthesis or lipolysis in WAT, muscle, or liver. There were no differences in WAT or skeletal muscle hydrolysis, uptake, and storage of [(3)H]triolein substrate [in situ lipoprotein lipase (LPL) activity]. ASP, however, increased in situ LPL activity in WAT (+64.8%, P = 0.02) but decreased it in muscle (-35.0%, P = 0.0002). In addition, after prelabeling WAT with [(3)H]oleate and [(14)C]glucose, ASP increased (3)H-lipid retention, [(3)H]TG synthesis, and [(3)H]TG-to-[(14)C]TG ratio, whereas it decreased (3)H-NEFA release, indicating increased NEFA trapping in WAT. Conversely, in muscle, ASP induced effects opposite to those in WAT and increased lipolysis, indicating reduced NEFA trapping within muscle by ASP (P < 0.05 for all parameters). In conclusion, novel data in this study suggest that 1) there is little intrinsic difference between KO and WT tissue in the parameters examined and 2) ASP differentially regulates in situ LPL activity and NEFA trapping in WAT and skeletal muscle, which may promote optimal insulin sensitivity in vivo.

Adipose Tissue↗

PubMed2004

Relationship between ghrelin and energy expenditure in healthy young women.

Ghrelin is a novel peptide that has been isolated from human and rat stomach tissues. Despite its known stimulatory effects on appetite and eating behavior, little information is available regarding its relationship with energy expenditure in normal-weight humans. To address this issue, we examined the relationship between serum ghrelin and resting metabolic rate (RMR), the thermic effect of food (TEF), fasting and postprandial respiratory quotient, physical activity level, peak aerobic capacity (VO(2 peak)), energy intake, and psychological measures of feeding behavior. We recruited 65 young healthy women and determined RMR and TEF by indirect calorimetry after a 12-h fast. Physical activity was determined by a leisure time physical activity questionnaire; VO(2 peak) was determined by bicycle ergometer test to exhaustion; energy intake was determined by a 24-h dietary recall; and food behavior was determined by a three-factor eating questionnaire. Our cohort showed a broad range of body mass index (range, 16.8-28.3 kg/m2), RMR (range, 820-1550 kcal/d), TEF (range, 74.4-136.5 kcal/d), and percent body fat (range, 14.0-37.7%). We noted significant inverse correlations between ghrelin and RMR (r = -0.350, P = 0.004) and TEF (r = -0.396, P = 0.001). These inverse correlations persisted after statistical control for both fat-free mass and fat mass (ghrelin vs. RMR partial, r = -0.284, P = 0.024; and ghrelin vs. TEF partial, r = -0.329, P = 0.01) and insulin levels (ghrelin vs. RMR partial, r = -0.255, P = 0.046; and ghrelin vs. TEF partial, r = -0.287, P = 0.024) using partial correlation analysis. We also observed a significant inverse correlation between ghrelin and daily caloric intake (r = -0.266, P = 0.032), but ghrelin levels were not significantly correlated with fasting (r = -0.002), postprandial respiratory quotient (r = -0.016), leisure time physical activity (r = 0.104), VO(2 peak) (r = 0.138), dietary disinhibition (r = -0.071), dietary restraint (r = 0.051), or feeling of general hunger (r = -0.028). These results suggest that higher levels of ghrelin are associated with low levels of resting and postprandial thermogenesis, which is independent of individual differences in fat-free mass and fat mass. Although speculative, serum ghrelin may play a role in the regulation of energy homeostasis by acting as a hormonal marker of increased energy efficiency.

Adult↗

PubMed2003

Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice.

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(-/-) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 +/- 2.4 m whereas KO mice moved 30.1 +/- 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT -68%, WAT -29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice.

Adipose Tissue↗

PubMed2003

Fasting acylation-stimulating protein is predictive of postprandial triglyceride clearance.

Postprandial plasma triglyceride (ppTG) and NEFA clearance were stratified by plasma acylation-stimulating protein (ASP) and gender to determine the contribution of fasting ASP in a normal population (70 men; 71 women). In the highest ASP tertile only, ASP decreased over 8 h (90 +/- 9.7 nM to 70 +/- 5.9 nM, P<0.05 males; 61.9 +/- 4.0 nM to 45.6 +/- 6.2 nM, P<0.01 females). Fasting ASP correlated positively with ppTG response. ppTG (P<0.0001, 2-way ANOVA, both genders) and NEFA levels progressively increased from lowest to highest ASP tertile, with the greatest differences in males. By stepwise multiple regression, the best prediction of ppTG was: (fasting ASP + apolipoprotein B + insulin + TG; r=0.806) for men and (fasting ASP + total cholesterol; r=0.574) for women. Leptin, body mass index, and other fasting variables did not improve the prediction. Thus, in men and women, ASP significantly predicted ppTG and NEFA clearance and, based on lower ASP, women may be more ASP sensitive than men. Plasma ASP may be useful as a fasting variable that will provide additional information regarding ppTG and NEFA clearance.

Blood Proteins↗

PubMed2003

Critical review of acylation-stimulating protein physiology in humans and rodents.

In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans.

Adipose Tissue↗

PubMed2003

The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein.

The orphan receptor C5L2 has recently been described as a high affinity binding protein for complement fragments C5a and C3a that, unlike the previously described C5a receptor (CD88), couples only weakly to G(i)-like G proteins (Cain, S. A., and Monk, P. N. (2002) J. Biol. Chem. 277, 7165-7169). Here we demonstrate that C5L2 binds the metabolites of C4a and C3a, C4a des-Arg(77), and C3a des-Arg(77) (also known as the acylation-stimulating protein or ASP) at a site distinct from the C5a binding site. The binding of these metabolites to C5L2 does not stimulate the degranulation of transfected rat basophilic leukemia cells either through endogenous rat G proteins or when co-transfected with human G(alpha 16). C3a des-Arg(77)/ASP and C3a can potently stimulate triglyceride synthesis in human skin fibroblasts and 3T3-L1 preadipocytes. Here we show that both cell types and human adipose tissue express C5L2 mRNA and that the human fibroblasts express C5L2 protein at the cell surface. This is the first demonstration of the expression of C5L2 in cells that bind and respond to C3a des-Arg(77)/ASP and C3a. Thus C5L2, a promiscuous complement fragment-binding protein with a high affinity site that binds C3a des-Arg(77)/ASP, may mediate the acylation-stimulating properties of this peptide.

Amino Acid Sequence↗

PubMed2003

ApoE phenotype influences plasma ASP in hyperapoB subjects.

Acylation stimulating protein (ASP) is increased in cardiovascular patients who often present with dyslipidemias. The aim of the present study was to examine the influence of apolipoprotein E (apoE) phenotype and lipids on ASP. Plasma ASP, lipids and apoE phenotype were measured in 407 subjects and separated according to the 75th percentile of apolipoprotein B (apoB) into a HyperapoB (HB) group (apoB=152+/-34 mg/dl, 117 men, 80 women) and a normal apoB (NB) group (apoB=88+/-19 mg/dl, 126 men, 84 women). Triglyceride (TG), cholesterol and LDL cholesterol were significantly increased in HB versus NB but there was no difference in age or body mass index (BMI). HB had increased ASP (42%>75th percentile, median=48.4 nM, P<0.001) versus NB (36.5 nM). There was no difference in ASP in NB with any apoE3 variant (E3/3=41 nM, n=98; E3/4=46 nM, n=55; E3/2=50 nM, n=41), but ASP was increased in E2/2 (126 nM, n=9), and E4/4 (186 nM, n=5, P<0.001 ANOVA). In HB, ASP was increased in three apoE phenotypes: E2/4 (209 nM, n=6), E2/2 (135 nM, n=6) and E4/4 (189 nM, n=26), P<0.001 ANOVA relative to the other apoE phenotypes (E3/3=50 nM, n=102; E3/4=41 nM, n=40; E3/2=87 nM, n=17) with a wide range of values. By stepwise regression analysis, the best model that predicted ASP was: [plasma non-esterified fatty acid (NEFA)+TG+cholesterol], where r=0.407, P=0.001. These data suggest that apoE phenotype may potentially influence ASP, although primarily in rare apoE phenotypes.

Apolipoproteins B↗

PubMed2003

Acylation-stimulating protein precursor proteins in adipose tissue in human obesity.

Recent reports have suggested a link between acylation-stimulating protein (ASP) and complement C3 with obesity, insulin resistance, coronary artery disease, and hyperlipidemia. Our aim was to examine the mRNA expression of C3 and other factors related to ASP production (such as factor B and adipsin) in adipose tissue. The influence of gender and obesity was examined in subcutaneous (SC) and omental (OM) tissues from 16 males and 16 females with body mass index (BMI) from 20 to 54 kg/m(2). The results demonstrate that factor B mRNA expression is higher in males than females in both SC and OM tissues. In female SC tissue, C3 and adipsin mRNA decrease with increasing BMI (r = 0.557, P =.025 and r = 0.717 P =.002, respectively), with no change in factor B. By contrast, in males there was a pronounced increase in C3, adipsin, and factor B in OM tissue with increasing BMI (r = 0.759 P =.001, r = 0.650 P =.006, and r = 0.568 P =.022, respectively). Of note, however, in both men and women there was a marked increase in the OM/SC ratio of C3 and adipsin with increasing BMI. These results suggest that in female SC adipose tissue, there is downregulation of factors related to ASP production in obesity, perhaps to limit further expansion of adipose tissue. In males, there is increased expression in OM tissue. In addition, relative OM/SC expression increases with obesity and these changes may contribute to the development of visceral adipose tissue.

Adipose Tissue↗

PubMed2003

Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects.

We examined fasting plasma insulin, acylation-stimulating protein (ASP), leptin, adiponectin, ghrelin, and metabolic/cardiovascular risk profile before and 15 +/- 6 months after isolated Roux-en-Y gastric bypass surgery in 50 morbidly obese subjects. Average preoperative plasma lipids were mostly normal, whereas ASP, insulin, and leptin were elevated, and adiponectin and ghrelin were decreased. Postoperatively, body weight decreased significantly (-36.4 +/- 9.6%) and was best predicted by preoperative adiponectin concentration in weight-stable subjects (r = -0.59; P = 0.02). Plasma lipids and insulin resistance improved, leptin and ASP decreased (-76.3 +/- 14.6% and -35.9 +/- 52.2%; P < 0.001), and adiponectin increased (50.1 +/- 47.0%; P < 0.001). The decrease in apolipoprotein B was best predicted by the decrease in ASP (r = 0.55; P = 0.009), whereas the improved postoperative insulin sensitivity was best predicted by the increase in adiponectin (r = 0.70; P = 0.01). Despite bypassing 95% of the stomach and isolating the fundus from contact with ingested nutrients, circulating ghrelin did not decrease after surgery. In fact, plasma ghrelin increased postoperatively in the subset of subjects undergoing active weight loss (+60.5 +/- 23.2%; P < 0.001); ghrelin, however, remained unchanged in weight-stable subjects. In summary, 1) preoperative adiponectin concentrations may be predictive of the extent of weight loss; 2) changes in ASP and adiponectin are predictive of decreased apolipoprotein B and improved insulin action, respectively; and 3) plasma ghrelin increases after gastric bypass surgery in patients experiencing active weight loss.

Adiponectin↗

PubMed2002

Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells.

This study determined the effects of apoA-I, HDL3, or hydroxy-beta-cyclodextrin on apoB-100 secretion and bile acid synthesis by HepG2 cells. The principal observations were that: 1) ApoB-100 secretion into the medium was significantly less after the addition of any of the three agents. 2) Triglyceride mass was not significantly changed from control in the medium but was significantly, although modestly, reduced in the cells. 3) Neither free cholesterol (FC) nor cholesteryl ester (CE) mass in the medium was changed; by contrast, CE mass was reduced within the cells although FC was not. 4) Although the total mass of cholesterol in the medium was unaffected, the proportion associated with apoB-100 was reduced, whereas the proportion associated with the non-apoB-100 fraction was increased. 5) There was also an unanticipated, but substantial, increase in bile acid synthesis induced by apoA-I, HDL3, or hydroxy-beta-cyclodextrin, which was time and concentration dependent, and which was associated with marked increases in cholesterol 7 alpha-hydroxylase activity. There were no significant changes in ACAT activity and only modest increases in HMG-CoA reductase activity. These findings support previous clinical observations that an elevated apoB-100 can accompany a low HDL cholesterol in normotriglyceridemic subjects. They also point to physiologically important, although still only partially understood, metabolic relationships amongst hepatic apoB-100 secretion, cholesterol efflux, and bile acid synthesis.

Apolipoprotein A-I↗

PubMed2002

Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice.

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. ASP administration results in more rapid postprandial lipid clearance. In mice, C3 (the precursor to ASP) knockout results in ASP deficiency and leads to reduced body fat and leptin levels. The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(-/-) double knockout mice (2KO). Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4-17 weeks age: male: -13.7%, female: -20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (-37.7%), suggesting increased insulin sensitivity. By contrast, food intake in 2KO mice was +9.1% higher over ob/ob mice (p < 0.001, 2KO 5.1 +/- 0.2 g/day, ob/ob 4.5 +/- 0.2 g/day, wild type 2.6 +/- 0.1 g/day). The hyperphagia/leanness was balanced by a 28.5% increase in energy expenditure (oxygen consumption: 2KO, 131 +/- 8.9 ml/h; ob/ob, 102 +/- 4.5 ml/h; p < 0.01; wild type, 144 +/- 8.9 ml/h). These results suggest that the ASP regulation of energy storage may influence energy expenditure and dynamic metabolic balance.

Animals↗