diabetes, lipids, and adipocyte secretagogues

REVIEW / SYNTHÈSE

Diabetes, lipids, and adipocyte secretagogues1,2

May Faraj, Hui Ling Lu, and Katherine Cianflone 190

Abstract: That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloadingof white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal andcardiac 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, cou-pled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is cru-cial, as highlighted by the disorders seen in both “too much” (obesity) and “too little” (lipodystrophy) white adiposetissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissueproducing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. Theconsequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues isjust beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulatingprotein, leptin, adiponectin, tumour necrosis factor α , interleukin-6, and resistin, defining their changes induced in obe-sity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.

Key words: C3adesarg, fatty acid trapping, lipolysis, lipogenesis.

Résumé : Il est bien reconnu que l’obésité est associée à une résistance à l’insuline et au diabète de type 2. La sur-charge du tissu adipeux blanc au delà de sa capacité de stockage entraîne des maladies lipidiques dans des tissus nonadipeux : les muscles squelettiques, le cœur, le pancréas et le foie. Ces effets sont souvent la conséquence d’une aug-mentation de l’apport d’acides gras non estérifiés. Cela entraîne une réponse insulinique anormale spécifique des tissus,ce qui augmente le dépôt de lipides et la lipotoxicité, associés à un profil lipoprotéique et (ou) métabolique plasma-tique anormal. Ainsi, il est crucial que les adipocytes fonctionnent adéquatement, comme l’indique les maladies causéespar trop (obésité) ou trop peu (lipodystrophie) de tissu adipeux blanc. Cependant, il est maintenant bien reconnu que,en plus de sa capacité d’emmagasiner les graisses, le tissu adipeux blanc est un tissu endocrinien produisant de nom-breuses hormones, et que les concentrations plasmatiques de ces hormones sont modifiées chez les personnes ayant unerésistance à l’insuline, diabétiques ou obèses. La conséquence de ces changements hormonaux sur le métabolisme duglucose et des lipides dans les tissus cibles de l’insuline commence à peine à être comprise. Cette revue porte principa-lement sur certaines de ces hormones : la protéine stimulant l’acylation, la leptine, l’adiponectine, le facteur de nécrosetumorale α , l’interleukine 6 et la résistine. Elle indique les changements des concentrations de ces hormones entraînéspar l’obésité et le diabète et met en relief les propriétés de ces hormones qui peuvent entraîner une détérioration dumétabolisme lipidique ou bien le protéger.

Mots clés : C3adesarg, stockage des acides gras, lipolyse, lipogenèse.

[Traduit par la Rédaction] Faraj et al.

Biochem. Cell Biol. 82: 170–190 (2004) doi: 10.1139/O03-078 © 2004 NRC Canada

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Received 5 September 2003. Revision received 20 November 2003. Accepted 25 November 2003. Published on the NRC ResearchPress Web site at http://bcb.nrc.ca on 27 January 2004.

Abbreviations: ApoB, apoprotein B; ASP, acylation stimulating protein; ATP, adenosine triphosphate; BMI, body mass index;cAMP, cyclic adenosine monophosphate; C3, complement 3; DM, diabetes mellitus; HDL, high-density lipoprotein; HSL, hormone-sensitive lipase; IL-6, interleukin-6; IRS-1, insulin receptor substrate-1; LDL, low-density lipoprotein; LPL, lipoprotein lipase;mRNA, messenger ribonucleic acid; NEFA, non-esterified fatty acids; TG, triglyceride; TNFα , tumor necrosis factor α ; UCP,uncoupling protein; WAT, white adipose tissue.

M. Faraj. Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Royal Victoria Hospital,687 Pine Ave. West, Montréal, QC H3A 1A1, Canada.H.L. Lu. Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.K. Cianflone.3 Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Royal VictoriaHospital, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada.

1This article is one of a selection of papers published in this Special Issue on Lipid Synthesis, Transport, and Signalling.2This paper has undergone the Journal’s usual peer review process.3Corresponding author (e-mail: [email protected]).

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A brief overview of obesity, insulinresistance, and diabetes

The prevalence of obesity is rapidly increasing in manycountries, even those such as China, traditionally protectedthrough diet, stressing the strong environmental influences.The increase in obesity, in turn, has lead to an increase in theprevalence of type II diabetes mellitus (DM) (non-insulin-dependent DM), as well as hypertension and cardiovasculardisease. This clustering of metabolic abnormalities associ-ated with obesity, insulin resistance, and cardiovascular dis-ease is generally referred to as the metabolic syndrome orsyndrome X. In its simplest equation, the increase in obesityis a consequence of positive energy balance: an increasedfood intake without a comparable increase in energy expen-diture. Factors that contribute to this include increased avail-ability and overconsumption of palatable energy-densefoods, decreased energy expenditure associated with seden-tary lifestyles, and decreased mobility in the workplace.Coupled to these environmental changes are the more subtlegenetic effects of “thrifty genes”, which may predispose cer-tain people or populations to increased efficiency of fat stor-age when excess food is available. Populations migratingfrom food shortage to food surplus environments, such asseen in Pima Indians, East Asians transplanted to Westerncountries, and present-day China often exhibit increased in-cidence of obesity and its associated comorbidity (Bennett1999; McKeigue 1996; Zhai et al. 2002).

As a consequence, hormonal regulation of energy expen-diture is just as important as that regulating energy storage,especially with respect to the partitioning of non-esterifiedfatty acids (NEFA). One focus of this review is to examinewhite adipose tissue (WAT) hormones that influence thecomponents of lipid metabolism (i.e., NEFA storage versusoxidation). One important characteristic of the developmentof DM is the gradual progression of insulin resistanceamong multiple tissues. Increased insulin resistance in WATmass is coupled to progressive reduction in insulin response,not only in WAT, but in all major insulin-responsive tissues,including muscle, liver, and pancreas. At a cellular level, in-sulin resistance translates into interference with the insulinsignalling pathways, including reductions in insulin receptorand insulin receptor substrate-1 (IRS-1) phosphorylation.Compromised metabolic functions extend beyond decreasedinsulin stimulated glucose disposal and failure of insulin tosuppress hepatic gluconeogenesis and secretion to includedefective lipid metabolism and altered WAT hormones secre-tion.

Energy homeostasis and fatty acid metabolismTo survive, all living organisms require a constant source

of energy. Because of the hydrophobic nature of lipids,NEFA circulate in the body complexed to albumin(Abumrad et al. 1999), while complex lipids circulate in theform of lipoproteins (micelles with an outer hydrophilicshell of phospholipids, cholesterol, and apoproteins (pro-teins) and an inner hydrophobic core of triglyceride (TG)and cholesterol esters). The apoprotein fraction of lipo-proteins (apoA, apoB, apoC, and apoE) renders lipids “solu-ble” in the blood, provides structural integrity to preventlipid dispersal en route to exchange or diffusion, and deliv-

ers lipoproteins to specific target tissues (Ginsberg 1998).The metabolism of TG is tightly integrated with that of car-bohydrates, mainly glucose. To be used, potential chemicalenergy that is stored in the C—H bond of NEFA and glu-cose is liberated upon oxidation in the mitochondria to car-bon dioxide (CO2) and water (H2O) and the production ofadenosine triphosphate (ATP) (7.3 kcal/mol of ATP gener-ated (1 cal = 4.1868 J)) (Stryer 1988). Triglycerides, how-ever, are much more energy dense than carbohydrates; thecomplete oxidation of a gram of TG generates 9 kcal andutilizes 2 L of oxygen (O2), whereas that of glucose provides4 kcal and utilizes less O2 (0.7 L O2/g) (Simonson andDeFronzo 1990).

The three major tissues involved in NEFA and glucosemetabolism in the human body are WAT, muscle, and liver.However, the regulation of substrate selection (NEFA versusglucose) and direction of energy transformation (catabolismversus anabolism) are highly dependent on the nutritionalstatus of the organism.

Fasting state versus postprandial stateIn the fasting or postabsorptive state, the mammalian body

is in a catabolic state (negative energy balance), and energyis extracted from the breakdown of endogenous stores. Thereare two main sources of NEFA in the fasting state: mobiliza-tion of the TG stores in WAT, and hydrolysis of the TG con-tent of very low-density lipoprotein (VLDL). Fastinghormones like glucagon and catecholamines activate hor-mone-sensitive lipase (HSL) in WAT through phos-phorylation by a cyclic adenosine monophosphate (cAMP)dependent protein kinase A pathway (Belfrage et al. 1985).HSL hydrolyzes TG droplets, releasing NEFA from WATthat circulate in the body to be taken up and oxidized by var-ious tissues. However, the circulating NEFA reservoir is lim-ited, and in humans, both tissue uptake and hepaticextraction maintain the plasma concentration of NEFA at0.1–0.8 mM (Pagana and Pagana 1997).

The flux of NEFA from WAT to the liver stimulates thesynthesis and secretion of apoB100-containing lipoproteins,mainly VLDL (TG-rich lipoproteins with an inner core of55%–80% TG) (Dixon and Ginsberg 1993). More NEFAmass can be carried around in this form, and in humans thefasting plasma concentration of TG is maintained at 0.4–1.5 mM (Barzilai et al. 1997). The catabolism of VLDL isinitiated by its interaction with endothelial lipoprotein lipase(LPL), where a series of complex reactions occurs involvinghydrolysis of the inner TG core, release of NEFA, exchangeof surface lipid components with high-density lipoprotein(HDL), and ending in the formation of VLDL remnants(Ginsberg 1998).

During the waking hours, human beings are rarely in afasting state. On average, healthy adult Canadians consume3–4 meals per day with an average total daily intake of1700 kcal for women and 2500 kcal for men, of which 30%is furnished by fat (Palaniappan et al. 2001). With the avail-ability of an exogenous energy source, HSL-mediatedlipolysis and gluconeogenesis are inhibited, while glycogensynthesis and lipogenesis are activated (Havel 2001; Kersten2001). This shift towards an anabolic state is highly drivenby diet-induced insulin secretion, which peaks within 30–60 min after consumption of a mixed meal (Havel 2001;

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Saleh et al. 1998). In vivo, an increase in the respiratoryquotient indicates a shift towards increasing carbohydrateoxidation (Faraj et al. 2001).

Dietary fat is packaged, along with other lipids and fat-soluble vitamins, in the enterocytes into chylomicrons(apoB48-containing lipoproteins with an inner TG core of80%–95%) (Ginsberg 1998). Postprandially, plasma TG con-centration increases by 2–2.5 times above fasting values(Bjorkegren et al. 1997; Faraj et al. 2001), of which 80% isaccounted for by chylomicrons (Cohn et al. 1993). Theclearance of chylomicrons involves the same series of com-plex reactions as for the clearance of VLDL, and is initiatedby endothelial LPL activity. Thus, hepatic VLDL and dietarychylomicrons are in continuous competition for binding siteson this enzyme.

Triglyceride clearance in peripheral tissueAt the peripheral site, initiation of the catabolism and

clearance of TG-rich lipoproteins requires the coordinationof two consecutive steps. The first step is governed by thecatalytic activity of endothelial LPL, which hydrolyzes theinner TG core of lipoproteins, generating NEFA and glyc-erol (or 2-monoacylglycerol). The second step involves theuptake and utilization of the NEFA according to the meta-bolic demand of the underlying cells (Fielding and Frayn1998). The close coordination of LPL activity and NEFA up-take and utilization is of utmost importance to ensure effi-cient TG clearance without oversupply of NEFA beyond theutilization capacity of nearby tissue, which would result indetrimental consequences (discussed below). In the fastingstate, LPL activity decreases in WAT, while increases inskeletal and cardiac muscles thus responding to the bodyneed of NEFA for oxidation. (Boivin et al. 1994; Doolittle etal. 1990; Fielding and Frayn 1998; Lithell et al. 1978; Picardet al. 1999). Reciprocal changes are also reported in muscleand WAT in the fed state, and muscle LPL activity is in-versely correlated to the insulin/glucagon concentration ratio(Picard et al. 1999). The “gate-keeping role” of LPL hypoth-esizes that an increased ratio of WAT to muscle LPL targetsNEFA towards storage and promotes obesity (Greenwood1985). This is evident in the association between obesity andincreased WAT LPL activity (Schwartz and Brunzell 1981).Furthermore, although not conclusive, it is postulated thatthe further increase of LPL with weight loss “pulls” NEFAtowards storage and favors weight regain (Kern et al. 1990;Schwartz and Brunzell 1981). On the other hand, increasingthe ratio of muscle to WAT LPL “sequesters” NEFA awayfrom fat deposition (Preiss-Landl et al. 2002). Evidence sup-porting this is that transgenic mice overexpressing LPL inmuscle are resistant to high-fat-diet-induced obesity andhave decreased plasma TG (Jensen et al. 1997). Moreover,genetically obese mice (leptin-deficient ob/ob mice) withspecific LPL deficiency in WAT have less weight and fatmass (Weinstock et al. 1997). In addition, LPL expression inskeletal muscle rescues LPL knockout mice from postnataldeath and decreases their plasma TG (Weinstock et al.1995); however, it does so only if LPL is catalytically active(Merkel et al. 1998). Finally, mutant mice overexpressingLPL in heart, skeletal muscle, and WAT are resistant to diet-induced hypercholesterolemia (on high-cholesterol diet) and

hypertriglyceridemia (on high-carbohydrate diet) (Shimadaet al. 1993).

Fatty-acid uptake and utilizationOnce the hydrolysis of chylomicrons and the VLDL TG

core is initiated by LPL, released NEFA are either taken upand utilized by underlying parenchymal cells or releasedinto the venous blood, where they bind to albumin. Frayn etal. (1995) have demonstrated through a series of elegant hu-man studies, measuring the arterial and venous drainage ofsubcutaneous abdominal WAT and forearm muscle, that thepartitioning of NEFA between tissue uptake and release intothe blood is a highly regulated process. After a mixed meal,LPL-derived NEFA trapping by subcutaneous WAT changedfrom close to zero at fasting to about 90% at 1 h after the in-gestion of a mixed meal (Frayn et al. 1995). More recently,using highly sensitive stable isotope techniques, it was dem-onstrated that the entrapment of LPL-derived NEFA by ab-dominal WAT was close to 100% at 1 h and decreased to10%–30% by 6 h postprandially (Evans et al. 2002). On theother hand, all NEFA released by the activity of skeletalmuscle LPL was taken up by the tissue at all times, as wassome of the remaining efflux of LPL-derived NEFA fromWAT (Evans et al. 2002).

Several models of NEFA transport and uptake into tissuehave been proposed: (i) transport of LPL-derived NEFA intoTG-synthesizing tissues (adipose tissue, liver, heart, andskeletal muscle) via lateral movement through a continuousinterface from the TG-rich lipoprotein surface film into theintracellular membranes of the parenchymal cells(Blanchette-Mackie and Scow 1976; Scow et al. 1980; Scowand Blanchette-Mackie 1991, 1992); (ii) active transport ofNEFA via membrane fatty acid transporters (Abumrad et al.1993, 1999; Berk et al. 1990; Schaffer and Lodish 1994);(iii) passive diffusion of circulating NEFA through a “flip-flop” mechanism that is driven by a concentration gradientacross the plasma membrane (Hamilton 1998). To date, theuptake of NEFA into tissues remains controversial. It is sug-gested, however, that under physiological conditions the ma-jority of NEFA uptake is mediated through active transportvia membrane proteins (Abumrad et al. 1999), while passiveNEFA diffusion may be more significant under higherNEFA/albumin ratios (i.e., under disease states such as insu-lin resistance). It is also possible that the model involved istissue specific (Eckel 1989).

Whether the source of NEFA is from the hydrolysis ofTG-rich lipoproteins, albumin-bound NEFA pool, de novofatty-acid synthesis, or lipolysis of endogenous TG stores,NEFA provide many essential functions in the body. Fattyacids activate K+ and Ca+2 channels in smooth and cardiacmuscle (Ordway et al. 1989; Philipson and Ward 1985) andcontrol the gene expression and activity of proteins specificto NEFA metabolism, such as fatty-acid transporters (FAT/CD36), acetyl-CoA synthase, and LPL (Amri et al. 1996;Grimaldi et al. 1992; Sfeir et al. 1997), which may be in-duced in part by binding to peroxisome proliferator activatedreceptors (PPAR) (Gustafsson 1998). Esterified fatty acidsare a required component for synthesis of many lipids, suchas TG, cholesterol esters, and phospholipids (Yamashita etal. 1997). The esterification of fatty acids to a glycerol back-bone “traps” this energy source safely within WAT until a

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shift in metabolic needs demands its release. Under condi-tions of negative energy balance, lipolysis within theadipocytes supplies required NEFA for various functions. Inmammals, the oxidation of NEFA in brown adipose tissue isutilized for thermogenesis and maintenance of a constantbody temperature through the activity of mitochondrial un-coupling proteins (UCP1, UCP2, and UCP3) (Carneheim etal. 1988; Klingenberg and Huang 1999). In tissues with highenergy demands, such as skeletal and cardiac muscles,whilst NEFA may enter the TG pool, its final fate is β-oxi-dation and the generation of ATP (Mead et al. 2002). In theliver, the influx of NEFA causes the synthesis and secretionof VLDL, which circulates in the body, providing a constantsource of energy when exogenous energy sources are limited(i.e., fasting state) (Dixon and Ginsberg 1993).

Obesity and defective fatty-acid trappingIrrespective of its etiology, energy intake in excess of en-

ergy expenditure will inevitably result in obesity. Obesity isdefined as body mass index (BMI) above 30 kg/m2, whereasmorbid obesity exceeds 40 kg/m2 (Hodge and Zimmet1994). The prevalence of obesity has increased in Canadaover the past 15 years from 8% to 14% in adult men andwomen, an increase that is alarmingly more pronounced inchildren (from 2% to 10% in children 7–13 years old)(Tremblay et al. 2002). Obesity is a complex metabolic state.Many obese individuals are perfectly healthy and never de-velop any abnormal metabolic profile. In fact, only about15%–20% of obese subjects ultimately become diabetic(Boden 2002). The reverse, however, is not true, as 67% oftype II DM patients are overweight (BMI ≥ 27 kg/m2) and46% are obese (BMI ≥ 30 kg/m2) (National Task Force onthe Prevention and Treatment of Obesity 2000). Althoughthe defects underlying the etiology of abnormal lipid metab-olism and insulin resistance in lean and obese subjects is un-known, it is generally accepted that elevated plasma NEFAconcentrations play a major role, an effect that is more pro-nounced with obesity.

White adipose tissue stores >95% of body TG and re-leases NEFA in proportion to its size and inability to trapNEFA as TG (Coppack et al. 1994). The balance betweenthe two metabolic and opposing processes in WAT, lipolysis,and lipogenesis defines the extent of NEFA release. A num-ber of studies demonstrate that insulin-mediated suppressionof lipolysis (by HSL) is defective in obese, insulin-resistant,and diabetic subjects (Campbell et al. 1994; Groop et al.1991). On the other hand, insufficient lipogenesis in WATwas also shown to contribute to increased NEFA releasefrom WAT. Insulin-resistant obese subjects were unable toswitch from negative to positive NEFA balance across WAT(or NEFA trapping) in the postprandial period, as is nor-mally observed in healthy lean individuals (despite the pres-ence of hyperinsulinemia) (Frayn et al. 1996). The reasonfor defective WAT lipogenesis in insulin-resistant obese sub-jects was suggested to be mediated by reduced insulin-stimulated glucose transport (precursor of TG–glycerolbackbone) and reduced insulin-stimulated DGAT activity(the rate-limiting step in TG synthesis) (Farese et al. 2000;Kahn and Flier 2000). Furthermore, in addition to their in-ability to trap NEFA in WAT, it was demonstrated that insu-lin-resistant obese and type II DM subjects have defective

regulation of postprandial LPL activity in response to insu-lin. These subjects show delayed stimulation of WAT LPLactivity and increased muscle LPL activity (instead of thedecrease normally observed) (Farese et al. 1991; Sadur et al.1984; Yost et al. 1995). In vitro, NEFA inhibit LPL activity(Amri et al. 1996; Olivecrona et al. 1995; Posner andDeSanctis 1987a, 1987b), interfere with binding of LPLboth to its activator apoC II and to heparin sulfateproteoglycan anchors (Saxena and Goldberg 1990), decreas-ing LPL transport to endothelial cells (Saxena et al. 1991)and displacing it from the endothelial cell surface(Olivecrona et al. 1995; Sasaki and Goldberg 1992; Saxenaet al. 1989). In vivo, rapid infusions of lipid emulsions,causing massive increases in plasma NEFA, displace LPLfrom endothelial surface and increase its activity in plasma(Peterson et al. 1990). Thus, in obese and insulin-resistantsubjects, increased total concentrations of NEFA due to re-duced NEFA uptake and increased endogenous lipolysis inWAT may further retard WAT LPL activity though productinhibition by NEFA.

Consequences of ineffective fatty-acid trapping in whiteadipose tissue

The importance of functional fat cells is crucial. Thus, theinability of WAT to trap NEFA, and WAT insulin resistance,particularly in the face of postprandial increased NEFA in-flux, leads to the diversion of NEFA to nonadipose tissues,mainly muscle, liver, and pancreas (as discussed below) andthe development of many metabolic abnormalities, whichfurther contribute to the insulin-resistance syndrome. An ex-treme condition of the detrimental effect of inefficient NEFAtrapping by WAT and the diversion of NEFA to nonadiposetissue is best appreciated in human disease (generalizedlipodystrophy and human immunodeficiency virus (HIV) re-lated lipodystrophy) and mouse models of lipodystrophy (re-duced peripheral WAT or complete absence of WAT). In thesemodels, plasma TG, glucose, and insulin are elevated; plasmaHDL cholesterol, leptin, and adiponectin are decreased; TGaccumulates in muscle and liver; and NEFA, rather than glu-cose, is preferentially oxidized by the muscle (Kim et al.2000; Misra and Garg 2003). Surgical implantation of WATpartially or completely reverses, in a dose-dependent fashion,hyperphagia, hyperglycemia, hyperinsulinemia, hypertri-glyceridemia, high plasma NEFA, muscle insulin resistance,and hepatic steatosis (Gavrilova et al. 2000). Moreover, insu-lin resistance is completely reversed by the combination ofphysiological doses of adiponectin and leptin; but it is onlypartially reversed by either hormone alone, which underlinesthe significance of these WAT hormones in the developmentof insulin resistance (Yamauchi et al. 2001).

MuscleIncreased flux of NEFA to the muscle activates

β-oxidation and inhibits glucose oxidation, an effect that oc-curs within minutes of elevated NEFA, as first described byRandle (substrate competition) (Randle et al. 1963). Two ad-ditional delayed effects later transpire: the first occurs within3–4 h and involves increased intramyocyte TG content withconcurrent onset of insulin resistance (Boden et al. 2001),and the second occurs within 4–6 h and involves inhibitionof glycogen synthase (Fig. 1) (Boden et al. 1994). Obese, in-

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sulin-resistant, and type II diabetic patients have impairedmuscle uptake and oxidation of circulating NEFA, whichmay be the primary defect leading to increased intramyocyteTG accumulation (Blaak et al. 2000; Simoneau et al. 1999).For an as yet unknown reason, muscle TG content correlateswith insulin resistance in humans and mice (Koyama et al.1997; Pan et al. 1997), and mice overexpressing muscle LPLhave a threefold increase in muscle TG and are insulin resis-tant (Pulawa and Eckel 2002). The abnormalities associatedwith increased muscle TG may, however, be a result of theincrease in TG metabolites (long-chain acyl-CoA and dia-cylglycerol). Acyl-CoA has been found to inhibit glycolyticenzymes (pyruvate dehydrogenase and phosphofructo-kinase), which leads to decreased glucose utilization, in-creased cellular glucose concentration, and, subsequently,decreased glucose uptake. Diacylglycerol interferes with in-sulin signaling and insulin-mediated glucose uptake (Pulawaand Eckel 2002). Thus, increased flux of peripheral NEFAcoupled to defective inhibition of muscle LPL by insulincontribute to increased NEFA uptake into muscle. This re-sults in insulin resistance via activation of protein kinase Cσ,alterations in gene expression, increased serine phosphoryl-ation of IRS-1 (which interferes with tyrosine phosphoryl-ation), and interference with insulin receptor phosphorylation(Kim et al. 2001).

LiverThe liver extracts plasma NEFA in proportion to their de-

livery rate (fractional extraction ~20%–30% (Wahren et al.1984)), and, thus, increased NEFA efflux from WAT causesincreased hepatic NEFA uptake. Hepatic NEFA influx inturn causes acute hepatic insulin resistance (i.e., lack of in-

sulin inhibition of endogenous glucose production) by inter-fering with insulin suppression of glycogenolysis (Fig. 1)(Boden et al. 2002). Similar to muscle, NEFA-inducedhepatic insulin resistance is associated with increased TGaccumulation (Ryysy et al. 2000). Moreover, in vitro studiesdemonstrate that hepatic NEFA influx per se decreaseshepatic insulin extraction and increases synthesis and secre-tion of VLDL by increasing precursor lipid substrates (TGand cholesterol ester) and increasing lipidation and secretionof apoB (Cianflone et al. 1990a; Dixon et al. 1991; Lewis etal. 2002). Many of these effects can be reproduced throughtissue specific overexpression of LPL in liver (Kim et al.2001).

In vivo, increased VLDL secretion leads to a series ofmetabolic abnormalities associated with obesity, insulin re-sistance, and DM, including decreased HDL cholesterol, in-creased small dense LDL, delayed postprandial chylomicronclearance, and increased hepatic uptake of LPL-derivedNEFA and TG-rich remnants (which further augment hepaticVLDL production) (Lewis et al. 2002). Moreover, NEFA de-creases binding of LDL to its receptor (Bihain et al. 1989).These findings, when taken together with reduced insulin-suppression of VLDL secretion, increased de novo NEFAsynthesis (with hyperglycemia), and reduced NEFA oxida-tion (inhibited by de novo lipogenesis), aggravate the effectsof hepatic NEFA influx in obese and insulin-resistant sub-jects (Jacqueminet et al. 2000; Lewis et al. 1993; Marques-Lopes et al. 2001). It is important to point out, however, thatthe detrimental effects of hepatic NEFA influx make abdom-inal or visceral obesity a greater liability than peripheralobestity. Although visceral fat depots are small in humans(~20% and 9% of total fat for men and women, respec-

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Fig. 1. Detrimental effects of defective NEFA trapping in WAT and increased NEFA efflux to muscle, liver, and pancreas. Increaseddietary TG influx with hyperphagia further aggravates the state of tissue insulin resistance. Solid lines represent induction, and dashedlines represent suppression of the indicated processes. In the muscle and pancreas, “….” represents the effect of long-term exposure tohigh NEFA flux.



tively), they drain directly into the portal vein, which repre-sents 80% of the total hepatic blood supply (Lewis et al.2002). Moreover, visceral fat represents a more rapidenergy-mobilizing depot, as it is more sensitive tocatecholamine-induced lipolysis and less sensitive to insulin-induced antilipolysis and NEFA re-esterification (Kahn andFlier 2000). Thus, visceral WAT may be a more hazardoussource of NEFA efflux to the liver and other tissues.

Pancreatic β cellsFinally, NEFA efflux from WAT impairs insulin secretion

by β-islets of the pancreas (Fig. 1). Acute NEFA concentra-tions (<6 h) increase insulin secretion in both in vitro and invivo models (Carpentier et al. 1999, 2000). However, withchronic exposure (>48 h), NEFA decreases glucose-stimulated insulin secretion and β-cell mass, leading to acondition known as β-cell lipotoxicity (Carpentier et al.1999; Unger 1995). The mechanisms leading to NEFA-induced β-cell lipotoxicity are numerous, including de-creased glucose transport into β-cell (decreased Glut 2),downregulation of protein kinase C (signaling pathway forinsulin release), and decreased insulin expression, synthesis,and processing (Chen and Reaven 1999; Jacqueminet et al.2000; Lewis et al. 2002; Zhou and Grill 1995). NEFA alsointerfere with glucose induced β-cell proliferation, causingstimulation of β-cell apoptosis (Lameloise et al. 2001). Invivo, prolonged elevation of plasma NEFA concentrations isproposed to impair β-cell ability to increase insulin secretionin response to decreased peripheral insulin sensitivity, an ob-servation that is most pronounced in obese subjects (Car-pentier et al. 1999, 2000). Most of these abnormalities havebeen linked to increased intracellular TG accumulation(Zhou et al. 1996), which is associated with β-cell dysfunc-tion in animal models (Carpentier et al. 1999; Unger 1995).In the context of concurrent hyperglycaemia (Briaud et al.2002; Harmon et al. 2001), there is an increase in lipogenicgene expression (Briaud et al. 2001) and increased islet TGmass (Zhou et al. 1996), with long-chain fatty acids beingthe most toxic (Kawai et al. 2001; Maedler et al. 2001). Fur-ther, intracellular TG can be hydrolyzed by HSL, resultingin an in situ supply of long-chain NEFA (Mulder et al.1999). That these TG deposits are associated with disorderedglucose metabolism is shown by studies that indicate thatantecedent hyperglycaemia but not hypertriglyceridemia is arequirement (Harmon et al. 2001). A further link to NEFAdysregulation of insulin secretion is the effect of uncouplingprotein (UCPs uncouple substrate oxidation from mitochon-drial ATP production and, hence, result in the loss of poten-tial energy as heat). Long-term exposure of β-cells to NEFAincreases UCP2 (homologue of the first identified uncou-pling protein, UCP1) and leads to changes in mitochondrialpotential, which alter glucose-stimulated insulin secretion(Maedler et al. 2001; Unger and Zhou 2001). Conversely,lack of UCP2 correlates with increased insulin secretion(Zhang et al. 2001). Thus, UCP2, through uncoupling anddecreased ATP production, may inhibit insulin secretion.Other than NEFA, lipid molecules such as LDL also furtherexacerbate the deterioration. LDL increases β-cells apoptosisthrough receptor-mediated uptake, which leads to lipid accu-mulation (Cnop et al. 2000, 2002).

In conclusion, WAT provides the “buffering” system tohandle the acute increase in NEFA influx with food intake.This buffering system, particularly in the face of increaseddietary NEFA influx with hyperphagia, prevents the detri-mental effects of high NEFA efflux to other peripheral tissuethat are unequipped to handle it in excess to its metabolicdemands.

Hormonal regulation of energy homeostasis and fatty-acid metabolism

Energy homeostasis is the flow of energy from intake toexpenditure, with the conservation of excess energy in theform of stored fat. The ability of the mammalian body tosense the switch between energy deficiency to energy sur-plus and to respond appropriately to ensure its survival re-quires the intricate coordination of many endocrine andneural metabolic signals. Many signals that control the regu-lation of short-term (fasting vs. fed) and long-term (weightloss vs. weight gain) energy homeostasis and NEFA metabo-lism have been identified. Some are derived from food itself,such as NEFA and glucose; others originate from a varietyof neural and endocrine tissues, including the hypothalamus,WAT, gastrointestinal tract, pancreas, and renal medulla.

Insulin is probably the earliest hormone known to regulatelipid metabolism and energy homeostasis, and it would beimpossible not to mention it in any discussion on this pro-cess. Insulin is secreted by β-cells of the pancreatic islets (is-lets of Langerhans), and its main target tissues are muscle,liver, WAT, and satiety centers in the hypothalamus(Figlewicz 2003). Insulin is involved in the regulation of en-ergy homeostasis and lipid metabolism by affecting all threecomponents: energy input (indicator and (or) regulator), oxi-dation, and storage.

Insulin is the main signal of the body to switch from afasting to a fed state, and it regulates postprandial energyclearance. The postprandial rise in circulating insulin en-hances peripheral utilization of all energy sources. In WAT,insulin stimulates LPL activity, NEFA uptake andesterification, glucose uptake and transport, de novo NEFAsynthesis, and TG synthesis, while it inhibits lipolysis (HSL)(Lewis et al. 2002; Zeman and Hansen 1991). In muscle, in-sulin (i) inhibits LPL activity, (ii) increases glucose andamino acid transport and glucose oxidation, and (iii) stimu-lates protein, glycogen, and TG synthesis (Lewis et al. 2002;Zeman and Hansen 1991). In the liver, insulin stimulatesglycogen, protein, TG, and de novo NEFA synthesis, whileit inhibits VLDL synthesis and secretion (acute effect),gluconeogenesis, glycogenolysis, proteolysis, and lipolysis(Lewis et al. 2002; Zeman and Hansen 1991). Moreover, in-sulin is an index of long-term positive energy balance, as itsconcentration is associated with the magnitude of adiposity.Fasting plasma insulin, as well as its postprandial response,is proportional to the degree of body adiposity (BMI, %body fat, body weight, waist-to-hip ratio), and obesity in hu-man and mouse models is associated with hyperinsulinemia,insulin resistance, and DM type II (Faraj et al. 2003; Havel2002; Zhang et al. 1994). Conversely, prolonged fasting,negative energy balance, and weight loss decrease plasmainsulin concentrations and enhance insulin sensitivity (Farajet al. 2003; Havel 2001).

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On the other hand, insulin is also a regulator of long-termenergy intake, as it exerts a negative feedback inhibition onfood consumption (Woods et al. 1979). To induce its effecton food intake, insulin is transported to the hypothalamus, aprocess that was shown to be slow, lasting for hours after thepostprandial plasma peak of insulin (Schwartz et al. 1991).Insulin transport to the hypothalamus is saturable at highconcentrations of plasma insulin (Schwartz et al. 1991).Obesity in rats (leptin receptor-deficient Zucker fa/fa rats)and other mammals is associated with impaired brain insulintransport and low cerebrospinal fluid insulin concentrations(Kaiyala et al. 2000; Stein et al. 1987), which might contrib-ute to obesity-associated hyperphagia. Thus, insulin regula-tion of energy balance involves short-term peripheralactivation of energy uptake and utilization (storage and oxi-dation) and long-term hypothalamic inhibition of food in-take. Chronic resistance to the hypothalamic actions ofinsulin may favour obesity, while conversely, there is noquestion that obesity leads to insulin resistance and DM.

Adipose tissue secretagogues and fatty-acid metabolism

In addition to alterations in insulin regulation in DM,there are abnormal levels in many serum proteins and hor-mones associated with various functions, such as inflamma-tory and endothelial functions including plasminogenactivator inhibitor-1, serum amyloid A, tissue plasminogenactivator, C-reactive protein, and others. Why these are al-tered in DM, and how this relates to their precise function isnot yet clear in many cases, although the documentedchanges in insulin resistance and DM have been consistentlydemonstrated. White adipose tissue is now recognised at thecenter of regulation of energy homeostasis, with autocrineand endocrine roles affecting many tissues. Thus, the re-mainder of this review will focus on the role of severaladipocyte hormones demonstrated to be altered in insulin re-sistance and DM, addressing specifically their potential rolesin alteration of fat homeostasis (storage or utilization):acylation stimulating protein (ASP), leptin, adiponectin, tu-mour necrosis factor (TNFα), interleukin-6 (IL-6), andresistin (Table 1). Many of these hormones influence thepartitioning of NEFA and lipids, either through redistribu-tion of TG mass among tissues (adipose, muscle, liver, andpancreas) or through rechannelling lipids between anabolic(TG storage) and catabolic (NEFA oxidation) pathways.

Note that this redistribution can result in either positive ornegative consequences.

Acylation-stimulating proteinAcylation-stimulating protein is the product of N-terminal

cleavage of complement C3 through its interaction with fac-tors B and D (or adipsin), generating C3a. C3a is thencleaved by carboxypeptidase, which is present in excess inhuman plasma, removing the carboxyl terminal arginine andgenerating C3adesArg or ASP (8932 Da) (Baldo et al.1993). Loss of terminal arginine renders the molecule withno known immunological function, in contrast to the precur-sor C3a that has anaphylatoxic activity (Hugli 1989). Thetertiary structure of C3a and ASP predicts a tightly linkedcore region consisting of three α-helices linked via threedisulphide bonds, which are essential for bioactivity, and acarboxyl terminal that extends from the core and may be in-volved in receptor binding (Murray et al. 1999a).

White adipose tissue is the only known site of productionof all three proteins required for ASP synthesis (C3, adipsin,and factor B) (Cianflone et al. 2003; Cianflone andMaslowska 1995). The expression of ASP precursors and theproduction of ASP in human adipocytes are induced in a dif-ferentiation-dependent manner, and occur after the increasein LPL expression and glycerol-3-phosphate dehydrogenaseactivity (two key enzymes in TG synthesis). However, thelipogenic capacity of the adipocytes markedly increases onlyafter the increase in ASP generation (Cianflone andMaslowska 1995). ASP generation from human adipocytesis stimulated by insulin (2-fold) and, to a much greater ex-tent, by chylomicrons (150-fold) (Maslowska et al. 1997a),specifically, through chylomicron-associated retinoic acid,which increases C3 mRNA transcription, protein synthesis,and secretion (Scantlebury et al. 1998, 2001). In humans, C3mRNA correlates with BMI, glucose disposal rate, andplasma TG, NEFA, and leptin (Koistinen et al. 2001). More-over, in in vitro models, the production of ASP precursors,C3, factor B, and adipsin has been shown to be regulated byTNFα, IL-1, IL-4, IL-6, and IL-17, aldosterone, estrogen,and glucocorticoids (Kalant et al. 2003a); and in vivo,cytokines (TNFα and IL-6) and glucocorticoids are proposedto regulate C3 and adipsin production in anorexic, obese,and coronary-heart-disease-prone subjects (Muscari et al.2000; Pomeroy et al. 1997; Weyer et al. 2000).

ASP enhances short-term energy clearance and fat stor-age. Human studies have demonstrated that fasting ASP cor-

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HormoneEffects on insulinsecretion

Plasma changesby insulin

Plasma changes indiabetes and insulinresistance Target tissues

ASP ↑ ↑ ↑ WAT, muscle, pancreas, hypothalamus (?)Leptin ↓ ↑ ↑ Hypothalamus, WAT, muscle, liver, pancreas, macrophageAdiponectin ? ↑ ↓ Muscle, liverTNFα ↓ ? ↑ (or) ↓ WAT, muscle, liver, pancreas, macrophageIL-6 ↑ ↓ (?) ↑ WAT, muscle, liver, pancreasResistin ? ? ↑ Liver, WAT

Table 1. White adipose tissue secretagogues. The target tissues of the white adipose tissue hormones ASP, leptin, adiponectin, tumornecrosis factor α (TNFα), interleukin-6 (IL-6), and resistin; their effects on insulin secretion (in humans and rodents); and the changesin their plasma concentrations induced by insulin, diabetes mellitus, and insulin resistance (in humans only). See text for referencesand details.



relates with postprandial TG clearance (Koistinen et al.2001). Postprandially, ASP is locally produced by WAT, asdemonstrated by examining arterial blood flow (“in”) andvenous drainage (“out”) of subcutaneous WAT (Kalant et al.2000; Saleh et al. 1998) despite unaltered or reduced post-prandial ASP in the general circulation (Charlesworth et al.1998; Faraj et al. 2001; Koistinen et al. 2001). This post-prandial increase in ASP production from WAT followed atemporal profile (3–5 h) that correlated with the increase inTG clearance and NEFA trapping across the same tissue(Kalant et al. 2000; Saleh et al. 1998). Conversely, loss ofthe ASP pathway is associated with postprandial hyper-lipidemia, as C3 knockout mice, thus obligatory ASP defi-cient, have delayed postprandial TG and NEFA clearance(Murray et al. 1999b, 1999c). This effect is independent ofthe leptin pathway, as ASP deficiency in leptin-deficientmice (ob/ob) also produces similar delays in postprandialTG clearance (Xia et al. 2002). Moreover, intraperitoneal in-jection of ASP enhances postprandial TG and glucose clear-ance in all mice models examined: wild type, ob/ob, db/db,C3 knockout, and double knockout (ob/ob–/– C3–/–) mice(Murray et al. 1999b, 1999d; Saleh et al. 2001; Xia et al.2002). Second, ASP may regulate energy expenditure. ASPdeficiency in ob/ob mice corrected the reduction of energyexpenditure usually observed in this obese (ob/ob) mousemodel (Xia et al. 2002). Increased energy expenditure inASP deficient mice was postulated to be a compensatorymechanism counterbalancing increased energy intake in theface of reduced lipogenic capacity of WAT (Xia et al. 2002).

Binding of ASP to cell-surface receptors was shown to bedirectly correlated with its capacity to stimulate TG synthe-sis (Cianflone et al. 1990b). Recently, a receptor for ASPhas been identified, C5L2, which is expressed at high levelsin human WAT as well as in human skin fibroblasts and3T3-L1 preadipocytes, cell models that are responsive toASP action (Kalant et al. 2003b). C5L2 (also known as G-protein coupled receptor 77) is also expressed in brain,heart, liver, and other tissues, although the ASP role in thesetissues has not yet been explored (Cain and Monk 2002; Leeet al. 2001).

The lipogenic effect of ASP has been demonstrated inmany cell models, including human skin fibroblasts, humanpreadipocytes, and adipocytes, and murine preadipocyte celllines 3T3-L1 (Baldo et al. 1993; Cianflone et al. 1989,1990b; Germinario et al. 1993; Kalant et al. 2003b; Walsh etal. 1989). The lipogenic activity of ASP is most pronouncedin human adipocytes (350% vs. 230% in preadipocytes) andis achieved through increasing the Vmax of TG synthesis(Cianflone et al. 1994). ASP increases TG synthesis in aconcentration- and time-dependent manner in two ways.First, ASP stimulates the activity of diacylglycerol acyl-transferase, the last and possibly the rate-limiting enzyme in-volved in TG synthesis; and, hence, it indirectly increasesNEFA uptake and esterification (Weselake et al. 2000;Yasruel et al. 1991). Second, ASP directly increases glucoseuptake in cultured human skin fibroblasts (Germinario et al.1993) and human adipocytes (Maslowska et al. 1997b). Inhuman adipocytes and fibroblasts, the signal transductionpathway by which ASP is postulated to increase NEFAesterification and TG synthesis involves the activation ofprotein kinase C (Baldo et al. 1995) and is independent but

additive to insulin (Germinario et al. 1993). ASP also de-creases NEFA release from human adipocytes (VanHarmelen et al. 1999) through increasing fractional re-esterification of NEFA (to the same extent as insulin) anddecreasing lipolysis (to a lesser extent than insulin). The sig-nal pathway proposed for both ASP and insulin involves ac-tivation of phosphodiesterase 3, and to a lesser extentphosphodiesterase 4 for ASP. Phosphodiesterase catabolizescAMP, decreasing local cAMP concentration and HSL ac-tivity (Van Harmelen et al. 1999). Taken together, thesefindings indicate that, in adipocytes, ASP markedly affectsthe reciprocal reactions of lipogenesis and lipolysis, the finalresult being decreased NEFA release and increased NEFAtrapping as storage TG.

ASP also stimulates glucose transport in L6 rat musclecells (Tao et al. 1997). Stimulating glucose uptake isachieved by increasing translocation of the glucose trans-porters (Glut 1, Glut 4, Glut 3) from intracellular vesicles tothe cell surface in a manner that is similar to insulin (Chiariet al. 1996; Germinario et al. 1993). However, the effects ofASP and insulin are again independent and additive, sug-gesting the involvement of different signalling pathways(Chiari et al. 1996; Germinario et al. 1993). Recently, anovel role of ASP in energy homeostasis was identifiedwhereby ASP increased glucose-mediated insulin secretionin insulin-producing clonal INS-1 cells and in pancreatic is-lets isolated from C57BL/6J mice (Ahren et al. 2003). ASPstimulation of insulin secretion is mediated by a direct ac-tion on pancreatic β-cells, an effect that is dependent on glu-cose phosphorylation, calcium uptake, and protein kinase C(Ahren et al. 2003).

ASP may also be a regulator of short-term food intake, al-though likely through a peripheral route. Intraperitoneal in-jection of ASP increased food intake in rats by 30% at 1 h,while intracerebrovascular injection produced a comparablebut more delayed effect (37% peaking at 2–4 h) (Saleh et al.2001). Of interest, the ASP receptor, C5L2, is expressed inhuman hypothalamus, the central nervous system locus ofappetite control (Lee et al. 2001).

ASP is an indicator of long-term positive energy balanceand abundance of energy stores. Plasma ASP correlates withbody weight and percent body fat (Maslowska et al. 1999;Sniderman et al. 1991; Weyer and Pratley 1999). It is ele-vated in human obesity (Cianflone et al. 1995; Koistinen etal. 2001; Maslowska et al. 1999; Sniderman et al. 1991;Weyer et al. 2000; Weyer and Pratley 1999) and decreasesproportionally with weight loss or prolonged fast (Cianfloneet al. 1995; Sniderman et al. 1991). Conversely, ASP-deficient mice have reduced fat mass and body weight, par-ticularly in females (Murray et al. 2000; Xia et al. 2002).ASP deficiency renders mice resistant to obesity in face ofincreased energy intake, such as on a high fat diet (Murrayet al. 2000) or in an obese background (ob/ob mice) (Xia etal. 2002) and results in reduced feed efficiency (weightgained/food intake) in C3 knockout mice (Murray et al.2000; Xia et al. 2002), suggesting that excess ASP may bepro-obesigenic.

While there are relatively few studies published on ASPlevels in diabetics, those few demonstrate that ASP is in-creased in DM, although this may be a consequence of obe-sity, since ASP correlates with body weight indices (BMI, %

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body fat) in these studies (Cianflone et al. 2003; Koistinen etal. 2001; Ozata et al. 2001). However, ASP also associateswith other diabetic plasma indices. Circulating levels of ASPcorrelate positively with plasma insulin (Koistinen et al.2001; Ylitalo et al. 2001), glycosylated hemoglobin (Ebelinget al. 1999), TG (Cianflone et al. 1997; Doolittle et al. 1990;Maslowska et al. 1999; Weyer and Pratley 1999; Ylitalo etal. 2001), NEFA (Cianflone et al. 1995; Doolittle et al.1990; Maslowska et al. 1999; Weyer and Pratley 1999), andapoB (Ylitalo et al. 2001) and negatively with glucose dis-posal rate (Koistinen et al. 2001). This suggests that elevatedplasma ASP is not only regulated by obesity but by DM-associated metabolic abnormalities as well. Moreover, treat-ment of diabetics with either thiozolidinediones orsulfonylurea drugs decreases glycosylated hemoglobin (in-dex of improved glycemic control), which was best pre-dicted by changes in plasma ASP and insulin, although therewas little change in body weight (Cianflone et al. 2003;Ebeling et al. 1999).

Alterations in plasma ASP in DM, coupled to the demon-strated cellular effects of ASP on lipid metabolism, maytherefore contribute to the lipid abnormalities associatedwith DM. While no study has yet examined the functionalresponse to ASP in “insulin-resistant” tissues, increasedplasma ASP may contribute to increased insulin secretion inislet β-cells, which would exacerbate the state of hyper-insulinemia and insulin resistance. On the other hand, chron-ically elevated ASP may lead to an ASP “resistant” stateaccompanied by reduced NEFA trapping in WAT and in-creased NEFA flux to other peripheral tissues such as liver.Fibroblasts isolated from hyperapoB patients (thus, withhigh hepatic NEFA influx) have reduced TG-synthesis ca-pacity in response to ASP. This effect was particularly evi-dent in a subgroup of patients with high plasma ASPassociated with reduced concentration of surface receptors,pointing to the possibility of ASP resistance in these patients(Cianflone et al. 1990b; Zhang et al. 1998).

Thus with a normal ASP pathway, WAT and ASP interactin an autocrine and endocrine positive feedback loop in-creasing ASP production, NEFA and glucose uptake andstorage, and possibly food intake to restore WAT stores andprevent its depletion. Conversely, in a chronic deficient ASPstate (C3 knockout), increased food intake may be a correc-tive mechanism employed by WAT to alleviate its inabilityto sufficiently stock TG stores, particularly when obesity isgenetically predetermined (C3 knockout mice in ob/obstrain). The efficiency of the ASP pathway and NEFA trap-ping within WAT, we hypothesize, may influence the lipo-protein and metabolic profile particularly in obesity asenergy intake exceeds expenditure and trapping of excessNEFA is of vital importance. A defective ASP pathway insome obese subjects, indicated by insufficient increase inplasma ASP in the face of increased dietary NEFA influx orby decrease in tissue ASP responsiveness (i.e., resistance)(or both these conditions), may favor insulin resistance andthe consequent metabolic abnormalities that evolve. Thiswould be associated by decreased TG clearance and NEFAtrapping in WAT and increased NEFA flux to muscle, liver,and pancreas, inducing hyperinsulenemia, insulin resistance,and hyperapoB. It should be pointed out, however, that astate of ASP deficiency need not be metabolically equal to a

state of ASP resistance. Both types I and II DM (insulindeficiency and insulin resistance, respectively) are character-ized by hyperglycemia, yet these disease conditions are as-sociated with different body composition and lipid profile.Untreated type I diabetic patients are underweight, with vir-tually no body fat, and develop ketoacidosis, whereas mosttype II patients are overweight (67%) and are resistant toketoacidosis (National Task Force on the Prevention andTreatment of Obesity 2000; Zeman and Hansen 1991). Theexistence of some insulin action, though reduced, in type IIDM is sufficient to preserve some glucose utilization, HSLinhibition, and lipogenesis (Zeman and Hansen 1991). Simi-larly, normal ASP action is characterized by efficient post-prandial TG clearance and NEFA trapping in WAT in bothmice and human models. Both extremities of ASP action(i.e., deficiency or resistance with overproduction) need notresult in the same degree of ineffective WAT NEFA trap-ping and the metabolic consequences that evolve.

LeptinLeptin, the product of the ob gene, was discovered in

1994 as the genetic mutation leading to obesity,hyperphagia, and insulin resistance in ob/ob mice (Zhang etal. 1994). It is a lipolytic hormone that is mainly synthesizedand secreted by WAT, although other sites like brown adi-pose tissue, skeletal muscle, stomach, and placenta havebeen identified as sources of synthesis and secretion ofleptin and its receptors (OB-R) (Fruhbeck et al. 2001).

Leptin production is regulated by nutritional signals and isan indicator of long-term energy surplus. Insulin stimulatesleptin expression, synthesis, and secretion (Bradley andCheatham 1999; Saladin et al. 1995), an effect that appearsto be dependent on insulin-stimulated glucose uptake andutilization (Mueller et al. 1998). High-fat diet reduces leptinlevels (Havel et al. 1999) possibly induced by decreased in-sulin. Short-term fasting, energy restriction, and weight lossalso decrease circulating leptin (Brichard et al. 2003; Dubucet al. 1998; Weigle et al. 1997) while refeeding, weight gain,and obesity increase plasma leptin levels (Havel et al. 1996;Kim and Scarpace 2003). In fact, body mass index and per-cent body fat are the best predictors of both leptin plasmaconcentration and its expression (Faraj et al. 2003; Havel2000). Finally, in human WAT, leptin exerts a negative feed-back regulation on its own expression (Wang et al. 1999a).Interestingly, while insulin increases leptin secretion and dis-ease states of elevated insulin (type II DM and insulin resis-tance) are characterized by hyperleptinemia, in contrast,leptin appears to inhibit insulin secretion from pancreaticcells (Seufert et al. 1999).

Like insulin and ASP, leptin regulates energy homeostasisby affecting its components: energy intake (indicator and(or) regulator), oxidation, and storage. The primary action ofleptin is on the central nervous system, reducing energy in-take and increasing energy expenditure, and this is mediatedthrough leptin receptors. Many isoforms of leptin receptorsexist (five forms) (Fruhbeck et al. 2001); only the full-lengthisoform (OB-Rb), primarily expressed in the hypothalamus,is believed to be involved in leptin signaling and bioactivity(center of appetite control) (Tartaglia et al. 1995). Humanand mouse models (ob/ob and db/db mice) with defectiveleptin pathways (leptin or its receptor) are severely hyper-

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phagic and obese (Clement et al. 2003; Montague et al.1997; Tartaglia et al. 1995; Zhang et al. 1994). Administra-tion of recombinant leptin reduces food intake and bodyweight in both human and mouse models (except db/dbmice) and increases physical activity and thermogenesis inmice (Campfield et al. 1995; Farooqi et al. 1999; Halaas etal. 1995). Leptin also increases energy expenditure throughactivation of the sympathetic nervous system, increasingnorepinephrine production in mammals (Tang-Christensen etal. 1999). Moreover, leptin increases whole-body glucoseutilization, decreases hepatic glycogen stores, and inhibits(with chronic exposure of >15 h) insulin-stimulated glucoseuptake and incorporation into lipids in mouse WAT (Ceddiaet al. 1998; Kamohara et al. 1997).

Beyond this, leptin directly targets peripheral tissues andalters fat metabolism. Recently, it was proposed that leptin isunable to cross the blood–brain barrier at supraphysiologicalconcentrations, yet mice made markedly hyperleptinemic(by adenovirus injection) nonetheless reduced their fat mass,suggesting that other extrahypothalamic mechanisms are in-volved (Wang et al. 1999b). Leptin treatment of rat WAT in-duced lipolysis, but of a novel form, where generated NEFAare channeled towards oxidation rather than release (Wang etal. 1999a; William et al. 2002). In rat WAT, leptin stimulatesthe expression of UCP-2, fatty-acid oxidation enzymes(carnitine palmitoyl transferase 1 and acyl-CoA oxidase),and their transcription factor (PPARα), a finding that mayexplain stimulation of NEFA oxidation by leptin (Wang etal. 1999a). Leptin increases substrate TG–NEFA cycling inWAT, stimulating the futile cycle and further “wasting” ATP(Reidy and Weber 2002). Moreover, leptin suppresses thelipogenic capacity of WAT by downregulating fatty acidsynthase expression and de novo fatty acid synthesis (Wanget al. 1999a; William et al. 2002). The peripheral effects ofleptin also extend to macrophages, where interaction ofleptin with the full-length isoform (OB-Rb) results in in-creased phosphoinositol (PI) 3 kinase activity and increasedJanus kinase (JAK2) and signal transducers and activators oftranscription (STAT3) phosphorylation, which results in in-creased HSL activity (as in adipocytes) (O’Rourke et al.2001). In macrophages, HSL acts as a cholesterol esterhydrolase, yielding an antiatherogenic stimulation of choles-terol ester breakdown. Finally, the unexpected finding ofhyperlipidemia in a double knockout mice of both the LDLreceptor and leptin suggests that leptin may also impactplasma cholesterol metabolism via an LDL-receptor-independent mechanism (Hasty et al. 2001). In the absenceof leptin, TG pools in the pancreas, heart, and muscle in-crease by 10- to 50-fold (Unger and Orci 2000). Transgenicoverexpression of leptin enhances the insulin response in amouse model of lipoatrophic DM (Ebihara et al. 2001;Simha et al. 2003). Thus, leptin may protect nonadipose tis-sue from TG accumulation and lipotoxicity by directly in-creasing NEFA oxidation and preventing NEFA-inducedupregulation of lipogenesis (Lee et al. 2000; Shimabukuro etal. 1997; Unger and Orci 2000, 2001; Zhou et al. 1999).

Thus, taken together, the autocrine–endocrine loop be-tween WAT and leptin opposes those of ASP and of insulin,resulting in decreased food intake, decreased fat storage, in-creased energy expenditure, and resistance to obesity. On theother hand, leptin levels, if anything, are increased in DM

(Fischer et al. 2002), possibly as a consequence of the com-mon presence of obesity. This suggests that, in addition toinsulin resistance, leptin resistance may be a common phe-nomenon in DM (Shintani et al. 2000). Further, increasedNEFA flux (as in high-fat diet) would not only lead to sup-pression of leptin secretion by WAT but also impair leptinsignalling in insulin-resistant states (Caro et al. 1996).

AdiponectinAdiponectin, also known as adipose most abundant gene

transcript 1 (apM1), adipoQ, and adipocyte complement re-lated protein of 30 kDa (ACRP30), was originally identifiedas the product of a highly induced gene after 3T3-L1 differ-entiation (Hu et al. 1996; Maeda et al. 1996; Scherer et al.1995). It is a relatively abundant plasma protein (~0.01% oftotal plasma proteins) that is exclusively synthesized and se-creted by WAT (Arita et al. 1999; Scherer et al. 1995). Aswith leptin and ASP, insulin increases adiponectin produc-tion and expression in human and murine adipocytes (Boganand Lodish 1999; Halleux et al. 2001).

Adiponectin has many metabolic actions involving periph-eral tissues and the regulation of energy homeostasis, partic-ularly energy expenditure. Adiponectin decreases plasmaglucose; increases clearance of a glucose load; and amelio-rates insulin resistance in mouse models with normal(C57Bl/6J), reduced (ob/ob, db/db), or absent (lipoatrophicmice) adiponectin pathways (Berg et al. 2001; Fruebis et al.2001; Yamauchi et al. 2001). Acute adiponectin administra-tion in mice reduces elevated postprandial NEFA resultingfrom ingestion of a high-fat test meal or intralipid intrave-nous injection (Fruebis et al. 2001). Daily administration ofadiponectin in mice on a high-fat–high-sucrose diet inducesmarked and sustainable weight loss without affecting foodintake, an effect that is concomitant with increased NEFAoxidation in muscle (Fruebis et al. 2001). Adiponectin de-creases muscle and liver TG content, increases gene expres-sion related to muscle NEFA uptake and utilization,increases muscle NEFA oxidation, and enhances hepatic in-sulin-mediated suppression of glucose production (as shownin isolated hepatocytes) (Harmon et al. 2001; Yamauchi etal. 2001, 2002). Accordingly, adiponectin knockout micedemonstrate insulin resistance after a glucose load or after ahigh-fat–high-sucrose diet (2 weeks), delayed NEFA clear-ance, and decreased expression of NEFA transporters inmuscle (Kubota et al. 2002; Maeda et al. 2002a, 2002b).

Adiponectin is the only known WAT derived hormonewhose levels are downregulated in obesity and DM. Humanand mice models of obesity and (or) insulin resistance (typeII DM and ob/ob mice) have reduced circulating adiponectinconcentrations and expression in WAT (Arita et al. 1999;Scherer et al. 1995; Statnick et al. 2000). In a recent studywith adolescents, plasma adiponectin was shown to correlatewith insulin sensitivity but was inversely proportional toplasma TG and intramyocellular lipid, suggesting one fur-ther functional link to insulin resistance (Weiss et al. 2003).Conversely, circulating adiponectin is elevated in humanmodels of prolonged negative energy balance namelyweight-reducing, type I diabetic and anorexic subjects(Brichard et al. 2003; Imagawa et al. 2002; Yang et al.2001). The suppression of adiponectin production with obe-sity may be mediated by an autocrine negative feedback in-

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hibition on the adiponectin pathway by WAT. Culturedhuman visceral WAT produces a factor that destabilizesadiponectin mRNA (Halleux et al. 2001), and microarraydata demonstrate that adiponectin expression is suppressedwith the development of obesity and DM in mice (Nadler etal. 2000).

Taken together, these studies suggest that adiponectin reg-ulates energy homeostasis by enhancing the uptake and oxi-dation of consumed energy (NEFA and (or) glucose),especially by muscle and liver. Although the adiponectingene is activated during adipogenesis (preadipocyte differen-tiation), autocrine feedback inhibition develops with obesityand DM, which, when coexisting with a state of defective in-sulin, ASP, and leptin pathways, further augments weightgain and the metabolic imbalance that evolves with obesity.

TNF�TNFα was first identified as a macrophage product impli-

cated in the metabolic abnormalities, insulin resistance, andweight loss associated with chronic infections and malig-nancy (Cerami et al. 1985). TNFα expression from WAT waslater described in mice and human models of obesity(Hotamisligil et al. 1993; Hotamisligil et al. 1995).Adipocytes are the predominant source of TNFα in WAT andexpress both types of TNFα receptors (Hotamisligil et al.1993; Ruan and Lodish 2003). Triglycerides and NEFA ap-pear to regulate TNFα production, as TNFα secretion fromWAT pads was increased following a high-fat diet (>45%fat) in rats (Morin et al. 1997). Similarly in humans, the in-crease in plasma TNFα concentrations following a high-fatmeal correlated with the increase in plasma TG (Nappo et al.2002a).

The association of TNFα with type II DM and insulin re-sistance has been well documented, as outlined by a numberof review articles (Kalant et al. 2003a; Ruan and Lodish2003; Sethi and Hotamisligil 1999). In rodents, TNFα pro-vides a link between obesity and insulin resistance, asclearly evidenced by the finding that TNFα knockout micefrom two obese mice models examined (diet-induced andob/ob obese mice) have significantly reduced NEFA concen-tration and improved insulin sensitivity (Uysal et al. 1997).Moreover, neutralizing TNFα increases insulin-mediatedglucose uptake in peripheral tissues in obese fa/fa rats (i.e.,improves insulin sensitivity) (Hotamisligil et al. 1993). Onthe other hand, in humans, the evidence that TNFα mediatesobese-induced insulin resistance is not well supported. Somestudies demonstrate that plasma TNFα, as well as TNFα ex-pression in WAT (Bullo et al. 2002) and skeletal muscle(Saghizadeh et al. 1996), are increased in DM (Grossi 2001;Jialal et al. 2002; Nappo et al. 2002b), although not in im-paired glucose tolerance (Kolb et al. 2002), and that plasmaTNFα decreases with weight loss in obese subjects (Bruun etal. 2003). Conversely, other studies show that despite in-creased expression of TNFα in WAT of obese subjects (withor without type II DM) and its correlation withhyperinsulinemia and BMI (Bullo et al. 2002; Hotamisligilet al. 1995), circulating TNFα concentrations (Hotamisligilet al. 1995) as well as in vivo TNFα secretion from subcuta-neous WAT were undetected (Mohamed-Ali et al. 1997).Furthermore, 4-week systemic administration of a TNFα-neutralizing antibody failed to decrease insulin resistance in

obese patients with established type II DM (Ofei et al.1996).

TNFα affects NEFA metabolism in a number of peripheraltissues by decreasing insulin secretion from pancreatic cells(Tsiotra et al. 2001) and insulin signalling in pancreaticcells, WAT, liver, and muscle (Grossi 2001; Tsiotra et al.2001). Specifically in WAT, TNFα stimulates lipolysis(Kalant et al. 2003a; Sethi and Hotamisligil 1999; Uysal etal. 1997), decreases adipocyte differentiation (Torti et al.1985), and suppresses the production of many factors thatare involved in TG accumulation: LPL, fatty-acid transportprotein, and acetyl CoA synthetase (Kalant et al. 2003a;Sethi and Hotamisligil 1999). Furthermore, TNFα inhibitsinsulin-mediated suppression of lipolysis (Uysal et al. 1997),reduces insulin-induced uptake of NEFA (Stahl et al. 2002),and decreases insulin-induced phosphorylation of insulin re-ceptor substrate-1 (IRS-1) and activation of phosphoinositol-3 kinase (Grimble 2002). Thus the net effect of TNFα is toreduce NEFA trapping in WAT by decreasing lipogenesisand promoting lipolysis and NEFA efflux. Interestingly,TNFα also stimulates the secretion of leptin (Sethi andHotamisligil 1999), while it suppresses the synthesis ofadiponectin from WAT (Steppan et al. 2001). These last ef-fects of TNFα (i.e., increasing the production of NEFA andleptin while decreasing that of adiponectin) will further aug-ment the inhibition of insulin secretion and reduction of in-sulin sensitivity (as discussed above). This highlights notonly the interaction between circulating NEFA, WAT hor-mones, and insulin resistance, but also the interplay amongthe discussed WAT secretagogues as well.

Interleukin-6Interleukin-6 (IL-6) is produced by a number of cells, in-

cluding monocytes and macrophages, fibroblasts, endothelialcells, smooth muscle, skeletal muscle cells, and WAT (Arikaet al. 1993; Febbraio and Pedersen 2002). Recently, it wasdemonstrated that up to 35% of the basal supply of IL-6 isderived from WAT (Mohamed-Ali et al. 1997). Thus, likemany cytokines, IL-6 is a widespread protein with produc-tion stimulated by a variety of physiological and pathologi-cal stimuli (Pedersen et al. 2001). IL-6 is increased in DM(Grossi 2001; Jialal et al. 2002; Kolb et al. 2002; van de Reeet al. 2003) and cardiovascular disease (Ridker et al. 2000)and after ingestion of a high-fat meal (Nappo et al. 2002b).While IL-6 decreases following the ingestion of a high-carbohydrate beverage (i.e., due to high plasma insulin)(Nieman et al. 2003), several studies have demonstrated thatIL-6 directly stimulates insulin secretion from a clonal cellline of hamster β-cells (HIT-T 15 cells) and rat pancreatic β-islets (Sandler et al. 1990; Shimizu et al. 1995, 2000). Thepositive association of IL-6 with insulin resistance and DMhas led to the suggestion that IL-6 is pro-insulin resistance(Kern et al. 2001; McCarty 1999; Pradhan et al. 2001).However the recent demonstration that IL-6 increases mark-edly in response to exercise has led to a re-evaluation of thepotential role of IL-6 in metabolism, as eloquently presentedin a recent review (Febbraio and Pedersen 2002).

In fact, IL-6 would appear to have positive effects inmaintaining metabolic homeostasis during periods of acuteenergy demand. Administration of IL-6 in rodents increasesblood glucose and decreases liver glycogen (Stith and Luo

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1994), while in humans IL-6 further increases hepatic glu-cose production (Stouthard et al. 1995). IL-6 increaseshepatocyte glucose release (Ritchie 1990) through inhibitionof glycogen synthase and acceleration of glycogen phos-phorylase activities (Kanemaki et al. 1998). There is also ev-idence that IL-6 may influence glucose uptake in insulinsensitive tissues such as muscle and adipocytes (Stouthard etal. 1995, 1996). These effects of IL-6 extend to NEFA me-tabolism: IL-6 infusion increases NEFA and serum TG(Stouthard et al. 1996), perhaps because of increased musclerequirements. Finally, IL-6 deficient mice (IL-6–/–) developmature-onset DM, higher basal glucose levels, and impairedglucose clearance, an effect that can be reversed through IL-6 injections (Wallenius et al. 2002). By contrast, over-expression of IL-6 in nonobese diabetic mice results indelayed onset of DM and prolonged survival (DiCosmo etal. 1994). This suggests a positive role for IL-6 in health. Asoutlined by Febbraio and Pedersen (2002), acute increases inIL-6 (such as after exercise) and chronic increases (such asin DM) should not be equated. This is similar to our under-standing of the consequences of acute versus chronic insulinincreases. They suggest that IL-6 may be chronically in-creased in disease (DM and cardiovascular disease) as a con-sequence rather than a cause. Increases IL-6 may beconsequent to obesity and increased total WAT productionor enhanced total body production may be an attempt tocompensate to downregulate other metabolic perturbations.In fact, IL-6 administration in humans induces the release ofsoluble TNFα receptors (Tilg et al. 1997) and may directlyinhibit production of TNFα (Febbraio and Pedersen 2002);both effects could counteract the detrimental effects of TNFα. Furthermore, as suggested by Febbraio and Pederson(2002), IL-6 expression may be upregulated in insulin resis-tant states to overcome the impaired glucose and NEFA me-tabolism and to enhance insulin sensitivity (Febbraio andPedersen 2002), and thus it has even been proposed that IL-6 should be considered as a potential therapeutic target(Febbraio and Pedersen 2002).

ResistinNo evaluation of WAT secretagogues and their role in DM

would be complete without addressing the topic of resistin.One of the newest members of the ever-increasing family ofadipokines, now with many research papers and many re-views published, the issue regarding resistin function re-mains clouded, as concisely presented in a recent review byHotamisligil (2003). Circumstantial evidence for the in-volvement of resistin in the pathology of insulin resistancedemonstrates that resistin increases with differentiation(Yamauchi et al. 2001) obesity (Yamauchi et al. 2001), DM(Mooradian 2001), high-fat diet (Kubota et al. 2002), andabdominal versus thigh WAT (McTernan et al. 2002a,2002b) and decreases with thiozolidinediones treatment(Hartman et al. 2002; Maeda et al. 2002b; Steppan et al.2001). The effect of insulin on resistin expression is alsocontroversial, as insulin was found to both decrease(Kawashima et al. 2003) and increase (Li et al. 2000)resistin expression in mice cell line 3T3-L1 adipocytes andin WAT from diabetic mice, respectively. Functionally invivo, resistin impairs glucose tolerance, decreases insulin-mediated glucose uptake, and increases hepatic glucose pro-

duction (Rajala et al. 2003; Yamauchi et al. 2001), while aneutralizing antibody normalizes glucose levels and tissueglucose uptake (Yamauchi et al. 2001). Evidence against arole for resistin in insulin resistance include the following:negative correlation of resistin with human adipocyte differ-entiation (Janke et al. 2002), obesity (Way et al. 2001), insu-lin resistance (Janke et al. 2002; Juan et al. 2001; Levy et al.2002; Savage et al. 2001), NEFA (Juan et al. 2001), andTNFα (Fasshauer et al. 2001; Shojima et al. 2002) coupledto increased resistin with β3-adrenergic agonists (Martinez etal. 2001), and fenofibrate treatment (Jove et al. 2003). Thus,in summary, the overall view of resistin remains controver-sial and its implication in fat metabolism undetermined.

Summary

Hormonal dysregulation in DM must include not only in-sulin and other circulating hormones, but also WATsecretagogues whose functions influence fat metabolism.The present review focuses on those that have demonstratedeffects on fat storage and oxidation: ASP, leptin,adiponectin, IL-6, TNFα, and resistin. Furthermore, many ofthese factors are associated not only with disordered insulinresponse, but also with dysregulation of the immune system,and extensive “cross-talk” between lipid-energy metabolismand the immune system has been noted repeatedly (Chen etal. 2002; Febbraio and Pedersen 2002). These similaritiesmay arise because of common overlapping “ancestry” of thecells from which the tissues are derived, or because of com-mon underlying functional similarities to protect and supplythe organism at a time of challenge.

There are several considerations to address relative to this.First, while plasma levels of all of these factors are influ-enced by diabetic status, it is difficult to decipher the contri-bution of body mass over DM, as most of these factors are(i) increased with adipocyte differentiation, (ii) producedprimarily by WAT, (iii) and increased in obesity, and(iv) type II diabetics are predominantly overweight and (or)obese. Second, as insulin is reported to increase the secre-tion of a number of these factors (as discussed above), thisraises the question of whether the increased insulin levels as-sociated with insulin resistance would lead to an increasedproduction of these adipokines, or would the WAT resistanceto insulin action extend to interference with hormone pro-duction?

On the other hand, as many of these hormones influenceinsulin production, will the altered levels also affect pancre-atic β-cell insulin secretion? While ASP, leptin, IL-6,resistin, and possibly TNFα are increased in DM, ASP andIL-6 increase insulin production, while TNFα and leptin in-hibits insulin production.

Furthermore, it is difficult to differentiate whether the in-creased levels of these adipokines, in association with insu-lin resistance, are a cause or a consequence of the diabeticdysregulation. Increased production of hormones such asTNFα may lead to augmented tissue response, resulting in adirect “cause” of insulin resistance due to interference notonly with insulin action, but with normal NEFA metabolismand hormone production (e.g., adiponectin). On the otherhand, the production of hormones may increase to compen-sate for diminished tissue response to either insulin or the

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hormone directly (i.e., ASP, leptin or adiponectin “resis-tance”).

In summary, insulin resistance and the centrality of WATneeds to be extended beyond these horizons to include thepotential metabolic effects of WAT secretagogues. The well-known disturbances in lipid metabolism in DM are a conse-quence not only of abnormal WAT responses, but extend toother peripheral tissues including muscle, liver, pancreas, en-dothelium, macrophages, and brain.

Acknowledgements

This work was supported by a grant from the CanadianInstitute of Health Research (MOP-13716) to KatherineCianflone. Katherine Cianflone is a research scholar of theFonds de Recherche en Santé du Quebec.

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