(AJ) Adipose tissue produces numerous adipokines, pro- and antiinflammatory cytokines and hormones which may influence the development of insulin resistance, type 2 diabetes mellitus and other comorbidities of the metabolic syndrome. The ability of adipose tissue to store lipids and thus protect other organs and tissues from ectopic lipid accumulation and development of insulin resistance (IR) is largely dependent on the adipogenic potential of preadipocytes. The amount and function of these cells may be the key factor in creating "healthy" adipose tissue or on the contrary "unhealthy" adipose tissue eventually leading to metabolic derangements. The regulation of the amount of body fat by converting preadipocytes into mature adipocytes may be crucial in the prevention and treatment of obesity and its comorbidities. One of the reasons for development of insulin resistance can be the inhibition of the differentiation process of preadipocytes into mature adipocytes with consequent ectopic lipid accumulation caused by the secretion of preadipocyte factor - 1 (Pref - 1). Pref - 1 has been discovered recently as a protein produced by preadipocytes but not by mature adipocytes. Pref - 1 is a member of the protein family sharing similarity with epidermal growth factors which regulate the differentiation of...

Title: Acipimox during Short-Term Exercise Exerts A Negative Feedback of Growth Hormone on Ghrelin Secretion in Patients with Bulimia Nervosa and in Healthy Women: The Role of Lipolysis Objective: Eating disorders, such as bulimia nervosa (BN) and anorexia nervosa (AN), are characterized by abnormal eating behavior. The main features of BN are binge-eating and inappropriate compensatory methods to prevent weight gain. The appetite-modulating peptide ghrelin is secreted by the stomach and shows a strong release of growth hormone (GH). A potential GH-ghrelin feedback loop between stomach and the pituitary has been recently reported. Acipimox (Aci), an analogue of nicotinic acid, inhibits lipolysis in adipose tissue (AT) and reduces plasma glycerol and free fatty acids (FFA) levels. Exercise and Aci are stimulators of GH secretion. We suppose that a negative feedback from increased GH levels during exercise may play a role in reducing plasma ghrelin levels. We surmised that altered baseline activity and exercise-induced activation of the sympathetic nervous system (SNS) results in excessive stimulation of lipolysis associated with negative energy balance and may lead to abnormal AT metabolism in patients with BN. Disruption of the gut-brain-AT axis might be involved in the pathogenesis of BN. The...

Hyperglycemia in critically ill patients was considered for many years an adaptive response to stress conditions being present in both patients with and without previous history of diabetes. Hyperglycemia is caused mainly by peripheral insulin resistance induced by the factors acting counteracting insulin signalling at the postreceptor level. Furthermore, hyperglycemia itself can then increase serum levels of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (Il-6) and interleukin-8 (Il- 8) and others. On the contrary, peripheral insulin resistance induced by pro- inflammatory cytokines may further potentiate hyperglycemia. White adipose tissue represents in addition to its energy storage function also a very active endocrine active organ. In addition to regulation of a number of metabolic processes it also significantly modulates the inflammatory response. In critically ill patients, adipose tissue changes its morphology, i.e. the adipocytes are shrinking and adipose tissue is abundantly infiltrated by macrophages. Paradoxically, overweight and obese critically ill patients have lower mortality than underweight, lean and morbidly obese subjects. In our studies, we selected population of the patients undergoing elective major cardiac surgery with extracorporeal...

(EN) GH/IGF-1 axis components (GH, growth hormone receptor (GH-R), IGF-1, IGF-1 receptor (IGF-1R), IGF-binding proteins (IGFBPs)) participate in the control of glucose metabolism, inflammatory processes as well as cell proliferation and differentiation, including adipocytes and monocytes. The aim of the present study was to evaluate the role of local mRNA expression of GH/IGF-1 axis components in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) in the development of insulin resistance and differences of adipose tissue mass in following groups of patients: obese females with and without type 2 diabetes mellitus and subjects with active untreated acromegaly. A total number of 66 subjects were included in the study: obese females without type 2 diabetes mellitus (OB), obese females with type 2 diabetes mellitus (T2DM), acromegalic patients (AC) and healthy lean control subjects (C). T2DM underwent 2 weeks of very-low- calorie diet (VLCD - energy content 2500 kJ/day). According to our results we suggest that decreased mRNA expression of IGF-1, IGF-1R, IGFBP-2 and IGFBP-3 in adipose tissue of T2DM subjects may contribute to changes of fat differentiation capacity and the increased IGF-1R mRNA expression in peripheral monocytes in these patients may play a role in the regulation of...

Excess food consumption and/or lack of exercise have dramatically contributed to the prevalence of overweight (BMI≥25) and obesity (BMI≥30) in modern society. The obesity epidemic has been linked to the rise in type 2 diabetes. In recent years, evidence has pointed to a close association between mitochondrial dysfunction in white adipose tissue (WAT) and insulin resistance, a key feature of type 2 diabetes. In order to dissect the cause and effect relationship between WAT mitochondrial dysfunction and insulin resistance, we established an in vitro cell line system to investigate this issue. We artificially introduced mitochondrial dysfunction in 3T3-L1 adipocytes by depleting the mitochondrial transcription factor A (Tfam) during adipogenesis, without changing the overall adipocyte differentiation program. We found that these Tfam-depleted 3T3-L1 adipocytes showed symptoms of insulin resistance, evidenced by impaired insulin stimulated GLUT4 translocation and glucose uptake. This result suggested that mitochondrial dysfunction could be a primary contributor to insulin resistance in fat tissue. However, the exact mechanism underlying this finding remains unclear. As part of a comprehensive understanding of insulin signaling in fat cells, we also investigated the involvement of the endosomal protein WDFY2 in the regulation of Akt isoform-specific effect on glucose uptake. In 3T3-L1 adipocytes, both Akt1 and Akt2 isoforms are expressed, but only Akt2 plays an indispensible role in insulin-stimulated GLUT4 translocation and glucose uptake. Previous studies implied that endosomal proteins may take a part in determining Akt substrate specificity. Here we found that WDFY2 preferentially co-localized with Akt2 and that knockdown of WDFY2 inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes, suggesting that endosomes are involved in this regulation. The effect of WDFY2 knockdown on insulin-stimulated glucose uptake worked through the down-regulation of Akt2, but not Akt1, protein level. We concluded that, endosomal protein WDFY2, by preferentially interacting with Akt2, regulates insulin signaling in glucose uptake in 3T3-L1 adipocytes. Our findings may help to develop specific therapeutic interventions for treatment of insulin resistance and type 2 diabetes.

During embryonic development, adipocytes emerge from microvasculature. Lineage-­‐tracing studies in mice have shown that adipocyte progenitors reside in the adipose tissue capillaries. However, the direct evidence of an association between adipocyte progenitors and vasculature in humans is lacking. A specific class of adipocytes (brown and beige/brite) expresses the uncoupling protein 1 (UCP1), which consumes glucose and fatty acids to generate heat. The abundance of UCP1- containing adipocytes correlates with a lean metabolically healthy phenotype in human. However, a causal relationship between the presence of these cells and metabolic benefits in human is not clear. In this thesis, I report human adipocyte progenitors proliferate in response to pro-angiogenic factors in association with adipose capillary networks in-vitro. The capillary-derived adipocytes transform from being UCP1-negative to positive upon adenylate cyclase activation, a defining feature of the brite/beige phenotype. Activated cells have denser, round mitochondria with UCP1 protein, and display uncoupled respiration. When implanted into NOD-scid IL2rgnull (NSG) mice, the adipocytes can form a vascularized fat pad that induces vascularization and becomes integrated into mouse circulatory system. In normal or high fat diet-fed NSG mice, activated brite/beige adipocytes enhance systemic glucose tolerance and improved hepatic steatosis, thus providing evidence for their potential therapeutic use. The adipocytes also express neuroendocrine and secretory factors such as Interleukin-33, proprotein convertase PCSK1 and proenkephalin PENK, which are correlated with human obesity. Finally, analyses on single-cell clones of capillary-sprout cells reveal the existence of diverse adipogenic progenitor populations. Further characterization of the clones will define the identifying features of the diverse adipocyte progenitor types that exist in human adipose tissue.

Obesity has increased globally in epidemic proportions and as have the associated disorders. Insulin resistance that could further lead to type 2 diabetes is a major obesity associated dysfunction. Studies using insulin resistant mouse models and observations from human subjects exhibiting insulin resistance provide evidence for ectopic lipid deposition in organs like liver, muscle and heart as one of the major risk factors for developing insulin resistance. These observations suggest that deregulated adipose function to sequester and store excess energy as fat, could lead to insulin resistance. Furthermore, several studies have demonstrated adipose tissue dysfunction leading to inflammation and related syndromes. Interestingly, a mouse model with transgenic expression of glucose transporter in the adipose tissue exhibited improved glucose tolerance and increased insulin sensitivity despite development of obesity, upon high fat feeding. Thus mechanisms that improve adipose function could alleviate insulin resistance and associated diseases. Mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) was identified in our laboratory as a negative regulator of adipocyte function. Interestingly, siRNA mediated knockdown of MAP4K4 promoted PPARγ protein expression. Additionally, silencing of MAP4K4 increased adipocyte triglyceride content. Because MAP4K4 is a negative regulator of PPARγ expression and adipocyte function, understanding the mechanism by which MAP4K4 regulates PPARγ expression is of interest. Thus, for the first part of this thesis, I characterized the signaling pathways utilized by MAP4K4 to regulate PPARγ expression in cultured adipocytes. Here I show that MAP4K4 regulates PPARγ expression through regulation of its protein translation. siRNA mediated MAP4K4 gene silencing stimulated PPARγ protein synthesis without changing its mRNA transcription or its protein degradation. This increase in PPARγ protein translation was due to an increase in the activity of mammalian target of rapamycin (mTOR). The increase in PPARγ protein expression mediated by mTOR activation was a specific effect of the 4E-BP1 phosphorylation that leads to its inactivation and was not a general increase in mTOR activity towards all of its substrates. Finally, adenovirus mediated over expression of MAP4K4 inhibited mTOR activation, and suppressed PPARγ protein translation. For the second part of this thesis, I assessed the role of MAP4K4 in adipocytes in vivo. To accomplish this, a lentivirus mediated shRNA construct was generated to attenuate MAP4K4 expression selectively in the mouse adipose tissue. First we demonstrate that the MAP4K4 shRNA construct is able to efficiently silence the expression of MAP4K4 in vitro when co-expressed with Cre recombinase. Furthermore, we show that following modification of the lentiviral conditional vector that was introduced into a mouse embryo at one cell stage, and crossing the resulting founders with aP2-Cre mice, adipose tissue specific MAP4K4 gene silencing was achieved. Moreover, shRNA mediated gene silencing is a faster and an inexpensive means of achieving tissue specific gene knockdown relative to the available traditional gene knockout approaches. Utilizing these adipose specific MAP4K4 gene knockdown mice, I reveal that MAP4K4 silencing enhanced fat mass as well as PPARγ expression significantly. This is accompanied by improved whole body insulin sensitivity. Furthermore, when challenged with high fat diet, adipose-specific MAP4K4 silenced mice exhibit enhanced adiposity with decreased lean mass. Moreover, adipocyte cell size and triglyceride content are significantly increased. Interestingly, despite increased adiposity, hepatic insulin sensitivity is significantly improved leading to decreased glucose output. Thus MAP4K4 is an important regulator of adipocyte function that mediates whole body glucose homeostasis, through a mechanism that is yet to be identified.

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing oligomer, a dual-component hydrogel system (cGEL) was established. First, hollow cGEL tubes were fabricated by a continuous dosing and templating process. Conduits were characterized concerning their mechanical strength, in vitro and in vivo degradation and biocompatibility. Second, cGEL was reformulated as injectable shear thinning filler for established NGCs, here tyrosine-derived polycarbonate-based braided conduits. Thereby, the formulation contained the small molecule LM11A-31. The biofunctionalized cGEL filler was assessed regarding building block integration, mechanical properties, in vitro cytotoxicity, and growth permissive effects on human adipose tissue-derived stem cells. A positive in vitro evaluation motivated further application of the filler material in a sciatic nerve defect. Compared to the empty conduit and pristine cGEL, the functionalization performed superior, though the autologous nerve graft remains the gold standard. In conclusion, LM11A-31 functionalized cGEL filler with extracellular matrix (ECM)-like characteristics and specific biochemical cues holds great potential to support PNR.

L'obésité est une épidémie mondiale qui augmente le risque de développer un diabète de type 2 ainsi que ses complications. Chez les individus obèses, le tissu adipeux sécrète de grandes quantités d'hormones et de cytokines qui affectent négativement le métabolisme du glucose et des lipides, ce qui provoque l'inflammation et la résistance à l'insuline. L'obésité augmente également l'activité du système rénine-angiotensine (RAS) localement au niveau de différents tissus et de façon systémique dans la circulation. L’angiotensinogène est convertie en angiotensine I par la rénine, ainsi que par la prorénine uniquement quand la prorénine est liée au récepteur de la rénine et prorénine [(P)RR] 1 . Ceci est la voie angiotensine-dépendante (Ang-D) du (P)RR. La liaison de la rénine et de la prorénine avec le (P)RR active également une voie angiotensine-indépendante (Ang-ND), ce qui produit une signalisation intracellulaire comportant la mitogen activated protein kinase (MAPK), la extracellular regulatory kinase 1/2 (ERK1/2), la promyelocytic leukemia zinc finger protein (PLZF) et le tumor necrosis factor alpha (TNF-a). Ceux-ci peuvent provoquer la croissance et la prolifération cellulaire, l'apoptose et la fibrose et pourraient donc être reliés aux dommages tissulaires et aux complications associées à l'obésité 1, 2. Plusieurs effets bénéfiques d’un blocage pharmacologique du (P)RR ont été rapportés tels la prévention du développement d'une fibrose cardiaque et rénale ainsi que la prévention de la néphropathie et de la rétinopathie diabétique. Cependant, les effets du (P)RR dans le tissu adipeux ont été peu étudiés. Par conséquent, notre objectif était d'étudier le rôle du (P)RR dans le développement de l'obésité et de la résistance à l'insuline par : 1) l'administration de HRP (un peptide bloquant l’effet du (P)RR) chez un modèle de souris obèse par l’administration d’une diète riche en gras (HFD), et 2) l’évaluation de souris ayant une délétion (KO) du gène (P)RR spécifiquement dans le tissu adipeux, qui a été généré dans notre laboratoire par la technologie Cre-LoxP. L'expression du gène et de la protéine du (P)RR dans les tissus adipeux était augmentée chez les souris nourries avec une HFD indépendamment du traitement au HRP. Le traitement par le HRP a réduit le poids corporel et la masse adipeuse chez les souris nourries avec une HFD alors qu’une tendance pouvait être observée chez les souris sur diète normale (ND). De façon similaire, les souris (P)RR KO spécifiquement dans le tissu adipeux avaient une réduction du poids corporel et de la masse adipeuse, même sur ND, ce qui suggère fortement l'implication du (P)RR dans le tissu adipeux dans le développement de l'obésité. Le phénotype des souris KO incluait une augmentation de l'activité horizontale uniquement dans leur période active, ce qui pourrait contribuer à augmenter leur métabolisme énergétique et ainsi réduire leur poids corporel et leur masse adipeuse. De plus, les souris KO homozygotes mâles avaient un métabolisme de base plus élevé car nous avons observé une augmentation de la consommation d'oxygène et de la production de dioxyde de carbone pendant leur période active et de sommeil. Cette augmentation du métabolisme pourrait résulter, en partie, d'une augmentation de la thermogenèse comme en témoigne l’expression accrue du gène de brunissement, PRDM16, dans le tissu adipeux péri-rénale de souris mâles KO. Conformément à cela, des résultats récents provenant de notre laboratoire ont également démontré que le HRP pouvait induire du brunissement au niveau du tissu adipeux sous-cutanée 3. Chez les souris traitées avec le HRP, bien que la glycémie eût été similaire aux souris recevant le placebo, l'insuline plasmatique et le rapport insuline/glucose était plus faible indépendamment de la diète. De façon similaire, les souris (P)RR KO avaient une insulinémie et un taux de peptide C plus faibles par rapport aux souris contrôles, sans aucune différence dans les courbes de la glycémie au cours d'un test de tolérance au glucose par voie orale. Les niveaux d'insuline dans l’état basal et stimulé étaient significativement plus faibles chez les souris KO, sans aucune modification du contenu pancréatique en insuline et du ratio insuline/peptide-C, ceci indique donc qu’il n’y a pas eu d’altération du niveau du métabolisme pancréatique de l'insuline. L’augmentation de l'adiponectine plasmatique chez les souris KO pourrait, entre autres, contribuer à une meilleure sensibilité à l'insuline observée. De plus, dans les groupes traités aux HRP, nous avons observé une amélioration du profil d'expression des gènes des transporteurs de glucose GLUT1 et GLUT4, du TNF-alpha, MCP-1, F4/80 et de la leptine dans le tissu adipeux ce qui pourrait contribuer à la meilleure sensibilité à l'insuline. Comme une meilleure sensibilité à l'insuline a été observée chez la souris suite au blocage pharmacologique et à la suppression génétique du (P)RR, ceci suggère que le (P)RR est impliqué dans la régulation de l’homéostasie du glucose. De plus, un taux circulant réduit des triglycérides (TG) a été observé chez les souris traitées au HRP, alors que des niveaux inférieurs de TG ont été trouvés seulement dans les muscles squelettiques chez les souris KO. Ces modifications du métabolisme des lipides et des taux circulants d'adiponectine résultent probablement d'un tissu adipeux plus sain tel que révélé par nos analyses histologiques démontrant une réduction de la taille des adipocytes chez les souris KO et traitées au HRP 3. Nos résultats démontrent que le (P)RR, en particulier dans le tissu adipeux, est impliqué dans la régulation du poids corporel et de l'homéostasie du glucose probablement par la modulation de la morphologie et de la fonction des adipocytes. Le développement d'une nouvelle stratégie clinique axée sur le blocage du (P)RR pourrait aider à traiter l'obésité et ses pathologies associées telles la résistance à l'insuline et le diabète de type 2. / Obesity is a worldwide epidemic and increases the risk of developing type 2 diabetes and its complications. In obesity, adipose tissue secretes large amounts of hormones and cytokines that negatively regulate glucose and lipid metabolism, causing inflammation and insulin resistance. Obesity also increases the activity of both local (tissue-specific) and circulating renin-angiotensin system (RAS). Angiotensinogen is converted to angiotensin I by renin, whereas prorenin may only do so upon binding to the (pro)renin receptor [(P)RR] 1. This is thus the angiotensin-dependent (Ang-D) pathway of the (P)RR. The binding of renin and prorenin with the (P)RR also activates an angiotensin-independent pathway (Ang-ND), leading to intracellular signaling involving, for instance, the mitogen activated protein kinase (MAPK), the extracellular regulatory kinase ½ (Erk1/2), the promyelocytic leukemia zinc finger protein (PLZF) and tumor necrosis factor alpha (TNF-a) 1, 2. These can produce cell growth and proliferation, apoptosis and fibrosis 1, 2, and as such may contribute to tissue damage and complications associated with obesity. The beneficial effects of pharmacological blockade of the (P)RR include prevention of the development of cardiac and renal fibrosis, as well as of diabetes-associated nephropathy and retinopathy. However, effects of the (P)RR in adipose tissue have been poorly investigated. Hence, our objective was to study the role of the (P)RR in the development of obesity and insulin resistance by: 1) administering HRP (a (P)RR blocker peptide) to mice fed a high-fat diet (HFD), and 2) in knock-out (KO) mice with adipose tissue-specific (P)RR gene deletion, which were generated in our laboratory by cre-loxp technology. (P)RR gene and protein expression in adipose tissue were increased in mice fed a HFD independently of HRP treatment. HRP treatment also reduced mice body weight and fat masses in HFD-fed mice while they only tended to be lower in mice on normal diet (ND). Similarly, the adipose tissue specific (P)RR KO mice had reduced body weight and fat masses, even on ND, and as such confirmed the involvement of adipose tissue (P)RR in the development of obesity. The KO phenotype included increased horizontal activity, only in the dark cycle (active period), which would increase energy expenditure and could contribute to their lower body weight and fat mass. Male hemizygous KO mice had higher basal metabolic rate as they had increased oxygen consumption and carbon dioxide production during both their active and inactive period. This increased basal metabolism may result in part from an increase in thermogenesis as increased “beiging” gene expression, PRDM16, was observed in peri-renal fat of male KO mice. In line with this, recent results from our laboratory have also shown that HRP may induce “beiging” in subcutaneous fat 3. In mice treated with the HRP, although glycemia was similar to placebo treated mice, plasma insulin and the insulin to glucose ratio were lower compared to untreated groups on both HFD or ND. Similarly, (P)RR KO mice had lower plasma insulin and C-peptide levels compared to controls, without any differences in the glycemia curves during an oral glucose tolerance test. Given that the basal and stimulated insulin levels were significantly lower in KO mice, without any changes in total pancreatic insulin content and with similar insulin to C-peptide ratio, this suggests that pancreatic insulin metabolism was not modified. The increased circulating adiponectin levels observed in KO mice may have contributed to the better insulin sensitivity present in the mice. In the HRP treated mice, we observed an improved gene expression profile of glucose transporters GLUT1 and GLUT4, TNF-alpha, MCP-1, F4/80 and leptin in adipose tissue, which may also contribute to the increased insulin sensitivity. Given that better insulin sensitivity was observed in mice with both (P)RR pharmacological blockade and genetic suppression, this suggests that the (P)RR is involved in the regulation of glucose homeostasis. In addition, lower circulating triglycerides (TG) levels were found in mice treated with HRP, whereas lower TG levels were observed only in skeletal muscles in (P)RR KO mice. Put altogether, the lower lipid content and higher plasma adiponectin levels likely result from a healthier fat tissue as revealed by histological analysis which showed a reduction in adipocytes size in KO mice and was recently revealed in HRP treated HFD fed mice 3. Our results demonstrate that the (P)RR, particularly in adipose tissue, is implicated in the regulation of body weight and glucose homeostasis via modulation of adipocytes morphology and function. The development of a new clinical strategy focused on blockade of the (P)RR specifically in adipose tissue could help to treat obesity and its associated pathologies such as insulin resistance and type 2 diabetes.

OBJECTIF: La mauvaise clairance des lipoprotéines riches en triglycérides par le tissu adipeux blanc (TAB) entraîne l’hypertriglycéridémie, la résistance à l’insuline et la sécrétion hépatique d’apolipoprotéine B (apoB). Ce mémoire tente de déterminer si le LDL entraîne une clairance réduite des lipoprotéines riches en triglycérides par le TAB. MÉTHODES/RÉSULTATS: Suivant l’ingestion d’un repas riche en gras marqué à la trioléine-13C, des femmes obèses postménopausées avec apoB plasmatique élevé (> médiane 0.93 g/L, N=22, 98% sous forme de IDL/LDL) avaient une clairance réduite de triglycérides-13C et acides gras non-estérifiés-13C (AGNE), comparées à celles avec un apoB plus bas. L'aire sous la courbe à 6 heures des triglycérides-13C et AGNE-13C plasmatiques corrélait avec l'apoB, suggérant une moindre captation dans les tissus périphériques chez les femmes avec apoB élevé. Ex vivo, suivant une incubation de 4 heures de biopsies de TAB avec de la trioléine-3H, l’apoB des patientes corrélait négativement avec les lipides-3H intracellulaires. Le traitement des biopsies de TAB des participantes avec leur propre LDL menait à une réduction de l’hydrolyse et de la captation de la trioléine-3H et à l’accumulation d’AGNE-3H dans le médium. In vitro, le LDL inhibait l’activité de la LPL. De plus, les adipocytes 3T3-L1 différenciés en présence de LDL avaient une hydrolyse et une captation réduite des lipoprotéines riches en trioléine-3H. CONCLUSION: Ce mémoire suggère que le LDL diminue la clairance des lipoprotéines riches en triglycérides par le TAB humain, ce qui pourrait expliquer la résistance à l’insuline observée chez des sujets avec apoB élevé. / OBJECTIVE: Delayed plasma clearance of postprandial triglyceride-rich lipoproteins (TRL) by white adipose tissue (WAT) promotes hypertriglyceridemia, insulin resistance and hepatic secretion of apoB-lipoproteins. The aim of this memoir was to examine whether low-density lipoproteins (LDL) induced delayed clearance of TRL by WAT. METHOD/RESULTS: Six hours following the ingestion of a high-fat meal, 22 postmenopausal obese women were separated based on plasma apoB levels (above/below median of 0.93 g/L). The high apoB group had delayed plasma clearance of postprandial triglyceride and non-esterified fatty acids (NEFA) compared to women with low apoB. There was no group difference in triolein oxidation rate, suggesting a lower NEFA uptake and storage in peripheral tissue in women with high apoB. Ex vivo, following a 4 hour incubation of participant’s WAT with synthetic 3H-triolein-TRL, plasma apoB correlated negatively with incorporated 3H-lipids. Incubation of women’s WAT with their own LDL (90% of apoB-lipoproteins in plasma) decreased 3H-TRL hydrolysis and increased medium 3H-NEFA accumulation. In vitro, LDL directly inhibited LPL activity. Finally, LDL-differentiated 3T3-L1 adipocytes had lower 3H-TRL hydrolysis and 3H-NEFA storage. CONCLUSION: This thesis suggests that LDL delay clearance and storage of TRL in human WAT, possibly explaining the increased insulin resistance observed in subjects with high apoB.