Cardiovascular disease accounts for 31% of all deaths in the United States. Understanding the mechanisms behind the development of this disease and how exercise may prevent, retard, or reverse disease progression may facilitate reduction in cardiovascular disease mortality. Although considerable research has used the laboratory rat, a more useful animal model for this research may be the swine. This review describes the advantages and disadvantages of the exercising swine model, examines atherosclerotic lesion development and lipoprotein profiles in exercising swine, and elaborates on current research investigating exercise-induced lipid mobilization from adipose tissue of swine.
Advantages. Swine have many anatomical and physiological similarities to humans, including a similar size, digestive tract, and cardiovascular system (26). Juvenile standard-size swine and adult miniature swine weigh 150 to 200 lb. They are monogastric and omnivorous, which make them particularly appropriate for nutrition studies(26). Their heart:body weight ratio of 0.005, the diameter of their coronary and iliac arteries, and the degree of collateral circulation of their heart are strikingly similar to humans(31,49,50).
Maximal oxygen consumption of swine is similar to that of humans, ranging from 25 to 55 mL O2/kg·min-1, whereas that of dogs ranges from 53 to 130 mL O2/kg·min-1(2,8,22). Swine will redistribute blood flow from visceral tissues to skeletal muscle during exercise(2,43). Like the human, acute exhaustive exercise causes severe metabolic acidosis in swine. This is not observed in dogs, suggesting that working muscles of swine either receive or extract insufficient oxygen to maintain a high level of aerobic metabolism(22). Biochemical responses to submaximal as well as exhaustive exercise in swine are qualitatively similar to those of humans, including changes in plasma pH, lactic acid, electrolytes, proteins, and catecholamines (51). Swine will adapt to exercise training by increasing muscle oxidative enzymes, maximal stroke volume, cardiac output, ˙VO2max, and serum or plasma high density lipoprotein cholesterol (HDL-C) levels, while decreasing resting heart rate and total cholesterol levels(31,38,39,41). Adaptations are seen after as little as 2 months of training; swine have been exercisetrained for as long as 2 yr (45).
The usual mode of exercise is treadmill running. Human treadmills equipped with variable speed and slope controls are suitable, with two modifications: wire enclosure around the treadmill to restrict lateral movement of the swine and rubberized belts on the treadmill surface to prevent hoof damage(41). The docile and compliant nature of swine makes them easy to train. With gentle handling, minimum stress, and gradual socialization, their benevolent nature secures them a place of value as a research animal (23).
Disadvantages. Potential problems for the exercise-training of swine include their development of hoof damage and their limited capacity to dissipate heat because of a low number of sweat glands(41). The latter potentially disadvantageous characteristic does make swine an appropriate model in which to study acute exertional heat exhaustion (17). Swine rely on panting and thermal conductance to remove excess heat (28). By exercising swine in an environment that is below 30°C and 70% relative humidity, misting the swine with cool water every 2 to 3 min, and using a rubberized belt on the treadmill, these potential problems can be circumvented.
ATHEROSCLEROSIS AND LIPOPROTEINS
Because of the similarities in the cardiovascular systems of swine and humans, the swine has become the experimental animal of choice for studying atherosclerosis (1,32). Swine will develop atherosclerotic lesions spontaneously, and lesion appearance in both the aorta and branch vessels of the heart can be exacerbated by feeding a high fat, high cholesterol diet (42). Aortic regions predisposed to early lesion formation can be highlighted by Evans blue dye, which is taken up into these regions after in vivo i.v. injection. This marker permits characterization of early atherosclerotic events such as low density lipoprotein cholesterol (LDL-C) accumulation and monocyte penetration(18). Advanced atherosclerotic lesions are characterized by regions of lipid-rich calcified debris, similar to what is seen in humans; these advanced necrotic lesions will regress to a more benign form if swine are fed a low fat, low cholesterol diet (33).
Lipoproteins: swine versus human. Swine have a similar serum lipoprotein profile to humans (Table 1)(30,46). Although fasting levels of total cholesterol and LDL-C are about one-half the value of humans, these levels will increase rapidly with a high fat, high cholesterol diet. Like the human, the major cholesterol-transporting lipoprotein in swine plasma is LDL. Because plasma LDL-C levels correlate directly with increased risk of ischemic heart disease, investigations have compared LDL composition and subfractions from swine with those from humans. Swine LDL has more protein and a higher density than human LDL, but apoprotein B-100 (apo B) comprises more than 95% of the LDL protein from both species (30,46). Using single spin density gradient centrifugation, three comparable LDL subfractions were isolated from swine and human serum; an additional fourth subfraction of higher density was isolated from swine serum (Table 2).
There are some noteworthy differences in lipoprotein metabolism between swine and humans. For example, only 10-16% of very low density lipoprotein(VLDL) apo B is converted to LDL apo B in swine, whereas nearly all VLDL apo B is converted to LDL apo B in humans (5,27). Swine also lack cholesteryl ester transfer activity, which is responsible for transferring cholesteryl esters between HDL and lower-density lipoproteins. There is no in vivo transfer of cholesteryl ester from LDL to HDL, but the reverse-transfer of HDL cholesteryl esters to LDL-has been demonstrated despite the swine's lack of the transfer activity(47).
Lipoproteins and exercise. A number of studies have examined the influence of exercise on plasma lipoprotein profile and atherosclerosis in the swine model. The results are mixed; one plausible explanation for this is that studies differed in the amount of exercise performed by the swine. This is illustrated in a comparison of five studies, shown in Table 3(14,16,34,45,48). Studies are arranged in order of increasing total exercise volume. As total exercise time increases, the lipoprotein and atherosclerosis responses improve. However, the conclusion that insufficient total exercise time is responsible for the negative findings of Gass et al. (16) and van Oort et al. (48) can only be conjectured, because these authors did not measure adaptation to exercise training such as˙VO2max or muscle oxidative enzymes.
The study by Stucchi et al. (45) warrants closer examination because it was long-term and thorough. When plasma concentrations of LDL, HDL, and VLDL were examined, there were no significant differences in response to exercise, possibly owing to variability in the data and the small sample size. However, there was a significant four-fold increase in HDL2-C level (Fig. 1, panels A and B); this subfraction has been suggested to inversely correlate with risk of heart disease (6). The increase in HDL2 levels may be a consequence of increased lipoprotein lipase activity with exercise training. There were also significant changes in LDL subclass composition(Fig. 2). Exercise caused significant reductions in the triglyceride content of LDL1 and LDL2, and a significant increase in free cholesterol content of LDL2. Thus research with this model supports the notion that exercise may decrease risk of atherosclerosis by inducing subtle changes in the composition of HDL and LDL.
Approximately 30% of an adult swine's body weight is fat, and one-half of this fat is subcutaneous, which is readily accessible. This permits longitudinal tissue sampling from the same animal for studies on subcutaneous adipose tissue metabolism. Thus the mechanisms by which exercise regulates cellular lipid mobilization can easily be studied in this model.
Hormones of lipid mobilization. The primary endogenous hormones that initiate lipid mobilization are epinephrine and norepinephrine. Both bind to the β-adrenergic receptor on the adipocyte surface that interacts with Gs to stimulate adenylyl cyclase. This initiates an intracellular cascade of events, culminating in the hydrolysis of triglyceride to free fatty acids and glycerol (see Fig. 3). Both products can enter the blood stream and serve as an energy source for other tissues of the body or, in the case of glycerol, as a glucose precursor in the liver.
The actions of the β-receptor can be opposed by either theα-receptor or the A1 adenosine receptor. Swine adipose tissue lacks α-receptor activity (with the exception of older, noncastrated males (9,40). The A1 adenosine receptor, however, is present in swine adipose tissue and when activated by adenosine binding, the receptor couples with Gi and inhibits adenylyl cyclase activity and the lipolytic cascade(12,25,44). There are scant data about the physiological relevance of adenosine and the A1 adenosine receptor in adipose tissue lipolysis. This lack of knowledge, coupled with our interest in understanding the role of exercise in regulating adipose tissue cellular metabolism led us to pursue the following three research questions.
Question 1. Since exercise increases lipid mobilization, our first question was: Does adipose tissue lipolytic sensitivity to adenosine, an antilipolytic agent, decrease after adaptation to endurance exercise? To address this question, we adapted 10 swine (4 females and 6 males) to running on a treadmill; a same-sex litter mate of each runner was assigned to a sedentary control group. By the end of 2 months, exercising swine were running 9 k·h-1, 45 min·d-1, 6 d·wk-1; they continued to run at this steady-state level for an additional month. At the end of the 3-month period, over-the-shoulder adipose tissue and brachialis muscle of each swine were biopsied; a significant increase in citrate synthase activity in brachialis muscle from exercised swine compared with controls confirmed that the swine had adapted to the endurance exercise. Adipose tissue was dissociated in collagenase and adipocytes were isolated and examined for in vitro lipolysis.
Rates of epinephrine-stimulated lipolysis failed to differ between the adipocytes from exercised versus control swine when glycerol production over a 90-min incubation period was expressed per cell number. However, adipocytes from exercised swine were significantly smaller than those from control swine so that a significant 37% increase in lipolytic rate in cells from exercised swine was observed when data were expressed per square centimeter surface area. Adipocytes were incubated with 1 μM epinephrine plus varying levels of phenylisopropyladenosine (PIA, a nonhydrolyzable analog of adenosine) to assess adenosine sensitivity. Adipocytes from five of the 10 exercisers demonstrated a rightward shift in the dose-response curve to PIA(Fig. 4); the concentration of PIA causing 50% inhibition of lipolysis was 64% greater in adipocytes from the 10 exercisers compared with those from the 10 controls. These data support the hypothesis that exercise-training reduces adipocyte sensitivity to adenosine, thereby facilitating fatty acid mobilization (7).
Question 2. The finding that adipocytes from exercised swine were less sensitive to adenosine than adipocytes from sedentary swine led us to our second question: What is the mechanism for the decrease in adipose tissue sensitivity to adenosine after endurance exercise? We suspected involvement of the adenosine A1 receptor, as this receptor is down regulated bothin vitro and in vivo(20,21,24,36). To investigate this possibility, we needed to establish that swine adipose tissue contains A1 adenosine receptors by developing a reliable assay system based on previous work done in the rat (35). After systematically examining for the influence of a variety of factors in the assay system including adenosine deaminase, EDTA, and CHAPS, we analyzed for[3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX) binding to swine adipocyte crude plasma membranes. Receptor number and binding affinity of swine adipocyte crude plasma membranes was found to be comparable to that from rats and human: Bmax was 479 ± 77 fmol·mg-1 protein and Kd was 0.87 ± 0.10 nM. In membranes from adipocytes of exercised swine, however, the Bmax was reduced by 50% to 239± 70 fmol·mg-1 protein; there was no change in binding affinity of the ligand for the receptor (12). These data support the notion that a decrease in A1 receptor number may be partly responsible for the reduced antilipolytic sensitivity of adipocytes from exercised swine to adenosine compared with controls.
Question 3. We are currently pursuing our third question: What is the source of extracellular adenosine? One possibility is extracellular cyclic AMP. Cyclic AMP has been shown to exit a variety of mammalian cells and tissues including erythrocytes, fibroblasts, astrocytoma cells, hepatocytes, cerebral cortex, and smooth muscle cells(3,4,10,11). Once outside the cell, cyclic AMP can be converted to AMP and adenosine(10,15,29,37). The resulting adenosine could bind to its receptor, inhibit adenylyl cyclase activity and reduce cyclic AMP synthesis, creating a “transmembrane negative feedback loop” as has been suggested in the kidney (29). Cyclic AMP egress has not been characterized in adipocytes, although cyclic AMP has been shown in vitro to exit hormonally-stimulated adipose tissue and to be metabolized to adenosine(19,52).
We are currently characterizing cyclic AMP egress from swine adipocytes. Adipocytes were isolated from 3- to 4-month old male swine and incubated in the absence or presence of three adenylyl cyclase stimulators: forskolin, isoproterenol, or epinephrine. At the end of 30 min, total and extracellular cyclic AMP levels were measured and intracellular cyclic AMP was determined by difference. A potential complication in this experimental design is adipocyte lysis: it could artificially elevate extracellular cyclic AMP levels by contributing intracellular cyclic AMP to the extracellular compartment. Therefore, cell lysis was monitored by measuring lactate dehydrogenase appearance in the extracellular compartment during the 30 min incubation, and extracellular cyclic AMP values were corrected accordingly.
Each of the compounds tested resulted in a significant increase in extracellular cyclic AMP level compared with unstimulated (basal) levels after correcting for cell lysis (Fig. 5). Forskolin, a potent stimulator of adenylyl cyclase, increased extracellular cyclic AMP levels 21-fold and intracellular cyclic AMP levels 5-fold compared with basal levels. Epinephrine and isoproterenol, β-adrenergic agonists, were less potent than forskolin in stimulating cyclic AMP appearance both inside and outside adipocytes (Fig. 5, unpublished observations, 1996).
Because cyclic AMP transport is a function of cell surface area, the effect of adipocyte size on cyclic AMP egress was evaluated in seven experiments in which mean swine body weights and cell diameters ranged from 9.5 to 16.6 kg and 58 to 83 μm, respectively (13). The wide variation in extracellular cyclic AMP levels expressed per cell number (145 to 250 pmol/106 adipocytes) decreased dramatically when cyclic AMP levels were expressed as a function of adipocyte surface area (97 to 121 pmol/cm2). Adipocyte surface area and cyclic AMP efflux were significantly correlated (r= 0.95). These data demonstrate that cyclic AMP is transported out of adipocytes and that this transport is a function of adipocyte size. Research is in progress to further characterize cyclic AMP transport out of adipocytes and the role that exercise plays in this process.
In summary, our studies on the effect of exercise on adipose tissue cellular metabolism suggest that adenosine has a role in regulating lipolysis. Adipocytes isolated from exercised swine are less sensitive to the antilipolytic effect of adenosine and have fewer adenosine A1 receptors on their cell surface compared with adipocytes from sedentary swine. Hormonally-stimulated adipocytes are capable of exporting cyclic AMP; whether this export plays a role in regulating lipolysis or is altered by exercise remains to be determined.
Because of its many similarities to humans, the swine is an excellent research model for studying the role of exercise on lipid metabolism at both the whole animal and cellular levels. The ease with which swine can be exercise trained and tissue samples can be procured permit well-controlled studies on exercise, atherosclerosis, and lipid metabolism.
The author wishes to graciously acknowledge research support from the NH Affiliate of the American Heart Association and NH Agricultural Experiment Station, Project H-346.
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Keywords:©1997The American College of Sports Medicine
LIPOPROTEINS; EXERCISE; ADIPOSE TISSUE; LIPID MOBILIZATION; ADENOSINE; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; PIG