Recent Advances in Nutritional Sciences

Comparative Aspects of LipidMetabolism: Impact onContemporary Research and Use ofAnimal Models1

Werner G. Bergen2 and Harry J. Mersmann3

Program in Cellular and Molecular Biosciences, Department ofAnimal Sciences, Auburn University, AL 36849

ABSTRACT The emerging obesity crisis and consequentconcerns for corrective measures and appropriate publicpolicy have stimulated research into causes, prevention,remediation, and health consequences of obesity and as-sociated maladies. Such research areas include eating be-havior, appetite control, and food intake regulation as wellas the regulation of lipid metabolism, cardiovascular func-tion, endocrine function, and dyslipidemia states utilizingvarious animal models and cell culture systems. Althoughthe liver has a central role in lipid/fatty acid synthesis andglucose is the precursor for de novo fatty acid synthesis inrodents and humans, in many other species, adipose tis-sues are the primary sites of lipogenesis. In addition, manyspecies utilize acetic acid as a precursor for fatty acidsynthesis. This fundamental difference in the site of fattyacid synthesis and the pattern of consequent lipid traffick-ing influences overall animal lipid metabolism and the roleof regulatory hormones and transcription factors. Re-searchers utilizing various animal species in targeted bio-medical research should be aware of these species differ-ences when interpreting their data. In addition, manyanimal species are used for food production, recreational,and companion purposes. Understanding the lipid metab-olism regulatory mechanisms of such species from a com-parative perspective is important for the proper nutritionand health of these animals. J. Nutr. 135: 2499–2502,2005.

KEY WORDS: ● lipogenesis ● lipolysis ● lipoproteins● species comparisons ● transcription factors

In the early 21st century, humanity finds itself facing bour-geoning medical problems related to overconsumption ofhighly available, energy-rich foods. This human culinary be-havior contributes to the onset of obesity, type 2 diabetes, andrelated cardiovascular maladies. Although there are emergingdata pointing to increased longevity upon energy restriction in

eukaryotic cell, insect, and animal models (1), unfortunatelyfor most overweight individuals, voluntary reductions in di-etary energy intake and needed lifestyle changes are difficult tomaintain for sustained periods of time. This emerging orpresent obesity crisis has prompted initiation of extensiveresearch efforts in areas such as eating behavior, appetitecontrol, and food intake regulation as well as in regulation oflipid metabolism, cardiovascular function, endocrine function,and dyslipidemia states utilizing various animal models andcell culture systems. This review will summarize various inter-species differences in lipid metabolism that may have to beconsidered when evaluating research findings from variousanimal models for application to human biology.

Comparative Lipid Biology: an Overview. Various animalspecies have been used to exploit their physiological unique-ness in addressing biomedical research issues, but too oftendifferences in lipid biology between animal species and hu-mans are not adequately considered in experimental designs.The availability of various animal models, in particular geneknockout and transgenic rodents, can make explorations ofthe role or function of a given or set of genes experimentallyrelatively straightforward and extremely useful in identifyinggene level relations between atherosclerosis and associatedmaladies (2). The question that is often not addressed, how-ever, is how data obtained with the “rodent model” apply toactual physiological/clinical settings in humans? In addition,there are numerous animal species that provide recreation orfood to humans. Many key aspects of lipid metabolism in thesespecies are not identical to rodents, but their lipid biology hasbeen studied not only from a biomedical perspective but alsoto apply such knowledge to agricultural production and animalhealth. For example, domestic pigs, because of their similarityto humans in body size and other physiological/anatomicalfeatures, including their innate tendency to overconsume food,have been used to study multiple aspects of atherosclerosis andcardiovascular disease (CVD)4 (3). In humans, obesity andCVD are typically associated with chronic, high-fat, excessenergy consumption but domesticated pigs, although omni-vores (4) in wild settings, consume a very carbohydrate-richdiet. In pigs, feeding a high-fat cholesterol diet results in theonset of atherosclerosis-like symptoms, which is of real benefitin experimental protocols in which the emphasis is on diseaseprogression and pathogenesis (5,6).

Sites of De Novo Synthesis of Fatty Acids andPrincipal Carbon Source in Animal Species. Althoughliver, adipose tissue, mammary gland, and intramuscular fatdepots have the capacity for de novo lipogenesis (DNL) (7–9),lipogenesis, cholesterol synthesis, lipoprotein synthesis andexport, and fatty acid oxidation have been investigated pri-

1 Manuscript received 18 July 2005.2 To whom correspondence should be addressed.

E-mail: bergewg@auburn.edu.3 Retired; formerly with U.S. Department of Agriculture, Agricultural Research

Service-Children’s Nutrition Research Center, Department of Pediatrics, BaylorCollege of Medicine, Houston, TX 77030.

4 Abbreviations used: �AR, �-adrenergic receptor; CVD, cardiovascular dis-ease; CLA, conjugated linoleic acid; DNL, de novo lipogenesis; FAS, fatty acidsynthase; NEFA, nonesterified long-chain fatty acids; PPAR�, peroxisomal pro-liferator–activated receptor �; SREBP-1c, sterol regulatory element binding pro-tein-1c.

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marily in rodent liver (8–10). Except in avian species in whichDNL occurs in the liver (7,11), DNL in many other animals iscentered in the adipose tissues. In addition, although glucoseis the principal carbon source for DNL in some species, aceticacid serves as the precursor for DNL in many other species.Use of acetate as substrate eliminates or modifies the role ofglucose transporters and carbohydrate-specific transacting fac-tors, such as carbohydrate responsive element binding protein(12) in the regulation of lipid metabolism. Table 1 presents acomparison of site of de novo lipogenesis (DNL) and carbonprecursor sources in humans, rodents, and various other spe-cies. For dogs, cats, pigs, cattle, sheep, and goats, DNL iscentered in adipose tissues (13–16), whereas in humans androdents, the liver is the primary site for DNL (7–9). Signifi-cantly, in animals with extensive forestomach and hindgutfermentations such as rabbits, cattle, sheep, and goats, a di-gestive tract fermentation end product, acetic acid, is theprincipal precursor for DNL (16). In addition, in species thatdo not metabolize glucose particularly well, e.g., cats, whichare carnivores (17), acetate appears to be the principal pre-cursor for DNL (14). Figure 1 depicts the pathways for DNLin utilizers of glucose and acetate irrespective of tissue speci-ficity. A principal difference between glucose utilizers andacetate utilizers is the path for fatty acid precursor carbon flow;in glucose utilizers, carbon flow is routed through the mito-chondria, whereas in acetate utilizers, acetate is activateddirectly in the cytosol (Fig 1). There appear to be no otherdifferences in the process of fatty acid synthesis, e.g., the rolesof cytosolic acetyl CoA carboxylase and fatty acid synthase aresimilar among all species.

Comparative Regulation of Lipid Metabolism inAdipocytes. Adipocyte lipid metabolism is modulated by anumber of endocrine, paracrine, and autocrine substances.The rodent adipocyte is unusually responsive to a wide varietyof endocrine entities including insulin, adrenergic hormones,thyrotrophin, somatotropin, adrenocorticotropin, thyroid hor-mones, and glucocorticoids. Adipocytes from other mamma-lian species exhibit less breadth of endocrine control withmeager or no demonstrable response to many of these hor-

mones (18). Regardless of species, insulin and the adrenergichormones are the primary acute controllers for mammalianadipocyte anabolic and catabolic lipid metabolism; other hor-mones have lesser effects, or more subtle chronic effects.Generally, insulin stimulates anabolic and inhibits cataboliclipid metabolism, whereas �-adrenergic receptor (�AR) ago-nists have the opposite effects (9,19). The physiological �ARagonists are the adrenal medullary hormones, epinephrine, andthe neurotransmitter norepinephrine. In addition, there aremany synthetic �AR agonists and antagonists used as phar-macological agents and in clinical settings (20). The rodentadipocyte responds dramatically to insulin with stimulation ofanabolic and inhibition of catabolic lipid metabolism. Smalleradipocytes, present to a large extent in young rats, have greaterfatty acid synthesis rates and insulin responsiveness than largeradipocytes, present to a greater extent in older rats (21). Ingeneral, ruminants are not very responsive to insulin, perhapsbecause glucose is only a minor substrate for fatty acid synthe-

TABLE 1

Organ/tissue sites of de novo fatty acid synthesis or lipogenesis (DNL) and primary carbon precursor sources in various species

Item

Species

Humans(Primates)

Rodents(Rats, Mice) Rabbits Pigs Dogs Cats

Avianspecies Cattle Sheep/Goats

PrimaryDNL-site

Liver Liver Liver/Adipose

Adipose Adipose Adipose Liver Adipose Adipose

SecondaryDNL-site

Adipose Adipose Liver Liver Mammary1 Mammary

Other Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Mammary;Muscle

Precursorfor DNL

Glucose Glucose Glucose/Acetate3

Glucose Acetate2/Glucose

Acetate2 Glucose Acetate3 Acetate3

Type ofdigestivesystem

SimpleStomach/Intestine

SimpleStomach/Intestine

SimpleStomach/IntestineHindgutfermentor

SimpleStomach/Intestine

SimpleStomach/Intestine

SimpleStomach/Intestine

SimpleStomach/Intestine

Ruminantforegutfermentor

Ruminantforegutfermentor

1 In lactating ruminants (especially dairy cows and goats), the mammary gland is a major site of DNL. All mammalian species exhibit mammaryDNL during lactation.

2 Preferred carbon source in dogs and cats for adipose tissue DNL (13, 14).3 In species with foregut or hindgut fermentation, acetic acid is the principal (or only) precursor for DNL.

FIGURE 1 Intracellular pathways of fatty acid carbon precursorsfor animals that utilize either glucose or acetic acid for de novo fattyacid synthesis.

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sis in these species (16). Under certain experimental condi-tions, however, bovine adipocytes may exhibit expected re-sponses to insulin (22).

Adipocytes from most mammalian species respond to �ARagonists quite well, with the most profound effects demonstra-ble on stimulation of catabolic lipid metabolism, i.e., lipolysis;the anabolic pathways are generally inhibited (19,23). Threesubtypes of �-adrenergic receptors (�1 AR, �2 AR, and �3AR) are usually observed in adipocytes. However, the subtypedistribution in various tissues, including the adipocyte, is spe-cies specific; the predominant rodent adipocyte receptor is the�3 AR (�90%), whereas in most other species, this subtype ispresent in very small numbers in adipocytes (usually �10%).Thus, the rodent adipocyte is controlled primarily by �3 AR,whereas this is not true in most other mammals (24). Further-more, the primary structure of the �AR subtypes varies withthe species, potentially imparting species specificity for re-sponses to synthetic �AR agonists and antagonists. For exam-ple, there is considerable stringency for the agonists and an-tagonists to stimulate or inhibit �AR in pigs, whereas therodent �ARs are stimulated or inhibited by a broad range ofagonists and antagonists (24). The �-adrenergic receptors,particularly the �2-receptors, work in opposition to the �AR,e.g., they inhibit lipolysis. In some species such as rats and pigs,the �2-adrenergic receptor function is difficult to demonstrate;in adipose tissue from other species, including humans, �2-adrenergic inhibition is marked (25).

Effects of Dietary Fatty Acids on Fatty Acid Synthesis.De novo fatty acid synthesis is inhibited by nonesterifiedlong-chain fatty acids [NEFA (26,27)] and cytosolic acetyl-CoA carboxylase activity is sensitive to feedback inhibitionfrom long-chain fatty acyl CoA in rodent liver (28). PUFA areparticularly effective inhibitors of rodent hepatic fatty acidsynthesis, whereas saturated NEFA have a lesser effect (26,27);a somewhat similar pattern is observed in rodent adipose tissue(26,29). These effects of PUFA are due largely to a reductionof mRNA for lipogenic enzymes at the transcription level(26,27). In contrast, in pigs with little hepatic DNL, adiposetissue DNL is inhibited by feeding fats containing predomi-nantly saturated or unsaturated fatty acids (30); in one study(31), palmitic acid was 2–3 times as effective as linoleic acid.Ruminants do not respond well to supplemental dietary lipidsin excess of 5% dietary dry matter because fatty acids interferewith reticulo-rumen anaerobic microbial digestive activity.Dietary fatty acids may be shunted to the small intestine inruminants by feeding rumen-protected lipids such as wholecottonseeds and fatty acid-calcium salts (32,33). Under suchconditions, supplemental fatty acids reduced DNL in adiposetissues and mammary glands of dairy cows (32,33).

During the last decade, there has been considerable interestin conjugated linoleic acids (CLAs), 18-carbon fatty acidanalogs of linoleic acid (34). The 2 double bonds in linoleicacid are cis-9, cis-12, whereas the common CLA isomers stud-ied are cis-9, trans-11, and trans-10, cis-12. Feeding of largeamounts of CLA to various species decreases adipose deposi-tion of fat, but in mice, this may be accompanied by increasedlipid accumulation in the liver; the 10,12-CLA isomer is theactive form for most of these effects (34). In mice or in rodentclonal adipocytes in culture, CLA increases metabolic rate andfatty acid oxidation, and decreases adipocyte hyperplasia anddifferentiation, fatty acid synthesis, lipoprotein lipase, andstearoyl CoA desaturase (34,35). Decreased fat deposition isobserved in other species, but the effects, including those inrats, are not as striking as in mice (35,36). Also, many of thepotential mechanisms for decreased fat deposition observed in

mice are difficult to demonstrate in other species or are incon-sistent (35). In ruminant species, the 9,11- and, to a lesserextent, 10,12-CLA isomers are produced during ruminal bio-hydrogenation of dietary PUFA and subsequent desaturationin various tissues, resulting in some deposition of CLA isomersin meat and milk from ruminant species (37). The 10,12-CLAisomer was causally linked with the milk fat depression syn-drome in lactating cows fed low-fiber, high-cereal grain diets(37). The 10,12-CLA isomer has now been shown to suppressexpression of mammary fatty acid synthase by attenuatingsterol regulatory element binding protein-1c (SREBP-1c) ex-pression and proteolytic processing (38). The effects of CLAin humans are marginal and difficult to demonstrate, perhapsbecause much lower levels were fed than in experimentalanimals.

Role of Transcription Factors in Lipid Metabolism. Thetranscription factor SREBP-1c (or ADD1) has an importantrole in the control of fatty acid synthase expression (10). Themost definitive data on the regulatory role of SREBP-1c inlipogenesis arise from SREBP-1c null mice, SREBP-1c over-expression, and negative-dominant SREBP-1c expressionstudies in rodents (10), but such data are lacking for mostspecies (11). Typically SREBP-1c and fatty acid synthase(FAS) genes are both expressed and correlated in tissues thatsynthesize fatty acids de novo (11). Thus, in chicken liver,SREBP-1c and FAS transcripts and proteins are elevated co-ordinately (7), whereas in pigs, SREBP-1c and FAS transcriptsand DNL are elevated in adipose tissue (11). In pigs, afterfeeding a commercial �-adrenergic agonist for �2 wk, adiposeexpression of both FAS and SREBP-1 were attenuated inparallel (39). In contrast, other findings, indicated that al-though adipocyte lipogenesis is highly correlated with insulinstatus (9), SREBP-1c mRNA abundance does not always co-incide with lipogenic activity (40).

It is generally considered that the transcription factor,peroxisomal proliferator-activated receptor � (PPAR�) con-trols the expression of fatty acid oxidative metabolism bymodulating the expression of peroxisomal acyl CoA oxidaseand mitochondrial carnitine palmitoyltransferase (41). Thistranscription factor and these enzymes are highly expressed inrodent liver and to only a modest extent in adipose tissue,giving rise to the concept that adipose tissue does not oxidizefatty acids to any extent. In pigs, there appears to be greaterexpression of PPAR� transcripts in adipose tissue than in liver(42,43), suggesting that in this species, and perhaps in othermammals as well, adipose tissue may oxidize sizeable quantitiesof fatty acids. Sundvold et al. (44), however, could not dem-onstrate PPAR� expression in porcine adipose tissues in theirextensive work. PPAR� is expressed in skeletal muscle; whenactivated, for example, by a fatty acid ligand, it promotes fattyacid oxidation, ketone body synthesis, and glucose sparing(41).

Comparative Aspects of Lipoproteins and LipidTrafficking. Lipids are transported in the blood plasma aslipoproteins, complexes of various lipid materials with specificproteins. The large chylomicron and VLDL contain consider-able amounts of triacylglycerol with small amounts of choles-terol. Chylomicrons are synthesized in the intestine and arefound in lymph and in plasma after a meal containing fat(45,46). Ruminant species have few or no chylomicron parti-cles because consumption of fats � 5% diet dry matter inter-feres with the rumen microbial feed digestion; under suchcircumstances, few long-chain fatty acids are absorbed (45).The LDL and HDL are the predominant carriers of cholesterol.

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Species differ in the proportion of the plasma cholesterol-containing lipoprotein, LDL and HDL (46,47). Guinea pigs,pigs, rabbits, and sheep transport most of the cholesterol inLDL, as do humans. Many potential animal models, in partic-ular rodents, carry the majority of cholesterol in HDL ratherthan LDL, making them less than desirable as models. Pigshave been a useful model for human atherogenesis, not onlybecause of many similarities in the lipoproteins, but also be-cause it is an omnivorous species, as are humans (4).

Coda. This short review provides evidence from the richliterature on comparative lipid metabolism that many differ-ences in lipid biology exist among species. Workers must becognizant of such differences whenever applying their resultsfrom various animal models to humans. This point is amplifiedin a recent report on novel mechanisms of PPAR� activation(48) in which the authors state, “In mammals, the liver inte-grates nutrient intake and delivery of carbohydrate and lipidsto peripheral tissues.” Clearly this is not correct for all mam-mals.

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