Experimental Studies

In vivo and in vitro studies

In vivo and in vitro studies have shown that PUFA, but not MUFA or SFA, seem to suppress the expression of genes involved in lipogenic transcription by decreasing the expression of the sterol regulatory element–binding proteins (SREBPs) (39,40,41). These studies were conducted on cells from hamster ovary or rat hepatocyte cell. The study of Worgall et al. (39) included PUFA from C18:2 to C22:6 and oleate. They found that oleate and PUFA decrease the transcription of SRE-regulated genes by 20–75%. Mater et al. (40) considered an isocaloric diet with different types of fat taken from lard, olive oil, corn, walnut, and fish oil in male rats. They demonstrated that all PUFAs down-regulate hepatic SREP-1 gene expression in vivo. The fatty acids administered by the Hannah et al. study (41) were oleate, linoleate, and arachidonic fatty acids. These authors demonstrated that PUFAs administrations down regulate the expression of SREP-1a and SREBP-1c. The mechanism explained by most of these studies, concerning the suppression of the expression of genes involved in lipogenic expression in SREBP, is that SREBP activates genes involved in adipocyte differentiation, in cholesterol synthesis and metabolism (42). Most fatty acids activate all of the peroxisome proliferator-activated receptor family (PPAR) at micromolar concentrations (43,44). PPARs transcription factors are key mediators of gene regulation in lipid metabolism (42,45). Moreover, PUFAs and particularly eicosapentaenoic and docosahexaenoic fatty acids seem to function as activator ligands for PPARs (45,46,47). PPARs genes are involved in adipocyte differentiation and lipid storage (45). They decrease adipose tissue mass and suppress development of obesity when activated (45). Although the induction of a high-fat oxidation rate by the consumption of PUFAs could influence energy utilization and fat deposition, the quantitative meaning of this assertion is presently unknown in humans (42). Results have demonstrated that PUFAs are better activators of PPAR- than MUFA or SFA. It seems that the highest binding affinity is completed with fatty acids containing 16–20 carbons. Also it has been reported that PUFAs are better activators of PPAR- than MUFA or SFA (43,44,48). The activities of all of these transcription factors have to be determined precisely as a function of the type of fatty acid intake. In vitro studies are helpful to explain the mechanisms of the associations observed in studies. They cannot be extrapolated in all cases to human or animal studies.

Animal studies

Animal studies have shown different rates of weight change in response to different types of fats in the diet (49,50). Rats were shown to oxidize linoleate more than palmitate (49). In rat liver, the oxidation rate of different fatty acids was as follows: linoleate > butyrate > linolenate > acetate > stearate (50). The general trend in animal studies is that the oxidation rate of the SFA decreases with increasing length of the carbon chains: laurate (72%) > myristique (58%) > palmitate (41%) > stearate (28%) (51).

For unsaturated long-chain fatty acids, there are suggestions in the literature that n-6 and n-3 PUFA have higher oxidation rates than does long-chain SFA (49). Additionally, after absorption, n-6 PUFA from safflower oil produces a greater thermogeneic effect (52), more oxygen consumption (53) and more sympathetic nervous stimulation (54). Some authors (52,54) have reported that when comparing safflower oil and beef tallow intake in rats, the latter group had a higher carcass fat content and a lower sympathetic nervous activity as well as a lower diet-induced thermogenesis.

PUFAs from fish oil can also decrease fat mass gain (55) and increases weight loss in rodents (56). Madsen et al. (23) stated that PUFAs from the n-3 group induce more effective control on PPAR- and in activating their genes than does n-6 PUFA. Moreover, n-3 PUFAs from marine sources seem to reduce adiposity more than n-3 PUFAs from plants such as -linolenic acid (57). On the contrary, Ailhaud et al. (17) reportedthat the inclusion of -linolenic acid in an isocaloric diet rich in linoleic acid prevented the increase of fat mass in a group of pups. These authors highlighted that these data were consistent with their previous results reported in vitro in which they were comparing the adipogenic effect of n-6 PUFA to that of n-3 PUFA. The mechanism proposed by investigators (who reported that n-3 PUFAs from marine sources reduce obesity in rodents) is that fish oil intake has been shown to increase the activity of carnitine acyltransferase I in rats (58), in mice (46), Syrian hamsters (59), and to inhibit malonyl-CoA activity (60) a key signal of satiety (61). The activation of carnitine acyltransferase I, as well as the inhibition of the synthesis of malonyl-CoA, seem to promote fatty acid availability for oxidation (47,59,62). Some authors demonstrated that with higher n-3/n-6 ratio intake, there was an increase in peroxisome and mitochondria B-oxidation in rodents (62). This was due to an increase in carnitine acyltransferase I activity. To note, not all studies demonstrated a decrease in fat mass and body weight in rats fed on fish oil (27).

There is some data that have shown that fat oxidation is higher with an increase in polyunsaturated/saturated (P/S) ratio intake (63,64). The explanation reported by most of these authors is that the morphology of villi in both rat jejunum and ileum is also affected by the ratio of P/S in the diet (63,64). In fact, villus surface area is increased with a diet high in PUFA (63). The study of Thomson et al. (63) was conducted in adult female rats. Isocaloric diets rich in palmitic, stearic, oleic, linoleic, and linolenic fatty acids were given. They demonstrated that jejunal uptake of medium-chain acid (C8:0–C12:0) was higher with the oleic acid than with other diet groups. Sagher et al. (64) reported that maize and olive oil increase villus height in both jejunum and ileum compared to butter oil in a group of rats fed isocaloric diets.

Few experiments studied the influence of dietary fatty acids with their deposition in Zucker fed a cafeteria diet (65). In Zucker obese rats, cafeteria feeding resulted in an alteration of enzymatic activities particularly in the conversion of linoleic fatty acid into dihomo-linolenic acid (65). Fat deposition was higher in rats given the cafeteria diet. In fact, cafeteria diet in lean and obese rats had shown a direct incorporation of dietary fatty acids into the rat lipids. On the contrary, the chow feeding in both groups activated lipogenesis and favored the deposition of shorter chain and more SFAs. Dang et al. (66) examined the effect of different diets (with 20% of energy derived from saturated, unsaturated or menhaden oil), on the phospholipid fatty acid composition and in vitro -5-desaturase activity of hepatic microsomes in the normal or streptozotocin-induced diabetic rat. The normal rat fed the saturated fat or menhaden oil diet had significantly decreased arachidonate levels in phospholipids, consistent with decreased -5-desaturase activities. On the other hand, the unsaturated fat diet decreased dihomo--linolenate and increased arachidonate levels in phospholipids, without increased -5-desaturase activity (66). Low levels of arachidonic acid, particularly in phospholipids, were observed in obese animals (45). Furthermore, PUFAs only, and not MUFAs or SFAs, seem to activate an isoform of SREBP, SREBP-1c, mRNA. The mechanism is still unknown (42). In rat liver, -5-desaturase is one of the targets of SREBP-1c. Docosahexaenoic fatty acid is the product of this desaturase when increased and is mostly incorporated into phospholipids and not in triglycerides (42).

Another mechanism that affects the utilization of SFA is the difference in stereoisomeric configuration of fat molecules (67,68). It seems that saturated dietary fat molecules, occupying sn-1 and sn-3 positions (coconut and palm oil), may be preferentially absorbed in comparison to those that are esterified on the sn-2 positions (milk and lard) (67). In fact, the former group may form insoluble calcium soaps in the human intestine (67). Some authors highlighted that insoluble calcium soaps lead to a decrease in the incorporation of fatty acids in chylomicrons, which will in turn deliver less lipids to the tissues and the plasma lipids (69). In contrast, some other investigators have not shown any significant difference in the absorption of dietary fatty acids subsequent to modifications of their stereoisomeric configuration structure (70). Most of these studies have been undertaken on animals and their physiological significance in humans is unclear. Additional research in this area is needed in human populations.

One should notice that animals, in most of these studies, are fed a standard laboratory diet supplemented with different fatty acids for various periods of time. The period of time of a given diet is an important factor to consider in animal studies. For instance, Marette et al. (49) reported a weight loss in rats only after 13 weeks when the rats were fed corn oil in comparison to the group of rats fed on a lard diet. In these studies, the quantity and the type of fat were well controlled. Authors tend to imitate the human diet when using laboratory animals such as rats, mice, or chicken but the human diet contains a great diversity of fatty acid profiles. Also, animals do not possess the exact same metabolism as do humans (23).

Human Studies

Metabolic studies

In Table 1, we summarized all the studies reported in literature that reported a positive, a negative, or an absence of association between dietary fat composition and weight change. We described outcomes as oxidation rate, weight change or fat deposition, energy expenditure and thermogenesis.

Table 1 - Metabolic studies in human on the association between dietary fat composition with change in body weight/body fat composition, rate oxidation, energy expenditure, or thermogenesis.

Full table (82K)

It is well known that short-chain fatty acids (C2:0–C4:0) and medium-chain fatty acids, MCFAs (C6:0–C12:0) are preferentially oxidized compared to long-chain fatty acids, C14:0–C24:0 (LCFAs), in humans as well as in animals (22,71,72,73,74,75). Short-chain fatty acid and MCFA are transported directly to the liver via the portal system (76,77). Short-chain fatty acid and MCFA are preferentially oxidized because they are not incorporated into esterified lipids and their transport to the mitochondrial matrix is not carnitine-dependent (76,77). Because of these properties, short-chain fatty acid and MCFA may lead to increased energy expenditure and contribute to a loss of adipose tissue in humans (74,78). Dulloo et al. (78) reported that when substituting LCFA with MCFA, in humans, at 15–30 g of fat/day, the energy expenditure is stimulated by 5% (500 kJ), which is partially mediated by the activation of the sympathetic nervous system. Therefore, these authors and others (79) stated that consumption of a diet rich in MCFA could lead to a reduction in final body weight. Others reported that MCFAs are poorly deposited within human tissues (80). In the adipose tissue, MCFAs are absent and they are less incorporated into hepatocytes and into adipocyte triglycerides than LCFA in humans and in animals (81,82,83). Some investigators also demonstrated (84) that the net energy value of MCFA is 5 kcal/g, which is different from the usual amount of energy coming from LCFA, 9 kcal/g.

The high rate of oxidation, the poor deposition of MCFAs in adipose tissue, their lower level of energy per gram available for metabolism, may explain the final body weight reduction reported in some studies when these types of fatty acids are consumed.

For long-chain unsaturated fatty acids, the MUFA type found in the human diet are: myristoleic (C14:1), palmitoleic (C16:1), oleic (C18:1), gadoleic (C20:1) and erucic (C22:1) acids. Oleic acid is the one that has been studied the most in literature for its association with weight change. This is the major fatty acid in olive oil, which in turn is one of the major components of the Mediterranean diet (85,86). Several studies in humans have shown that oxidation of MUFA, especially oleate, was higher than linoleate, which in turn was greater than stearate or palmitate (87,88,89). In addition, several clinical trials with one exception (30) reported that oleate is oxidized to a greater extent than palmitate, particularly in obese individuals (90). In their randomized study Lovejoy et al. (30) administered a diet with 28% of energy from fat. Authors compared MUFA (oleic), SFA (palmitic) and trans fatty acids (elaidic) in 25 healthy men and women.

In studies that reported a higher oxidation rate with MUFA intake (87,88,89), the mechanism proposed by most of the authors is that MUFA intake increases diet-induced thermogenesis which in turn stimulates the sympathetic nervous system. Abdominally, obese subjects may be more responsive to the stimulation of the sympathetic nervous system because they have an increased density and sensitivity of B-adrenoreceptors (91). Furthermore, abdominal, more than femoral adipocytes, have greater lipolytic response to catecholamines (91). However, some authors compared the substitution of a high MUFA diet with an energy-restricted diet (92,93) but did not find any significant difference in body weight in either group. Clifton et al. (92) reported a conservation of lean body mass with a diet rich in MUFA. In this last randomized study, 62 women with type 2 diabetes were observed for 12 weeks. Thirty-five percent of energy was given to the group of women following the MUFA rich diet and 12% of total fat was given to the group of women following the low-fat diet. Pelkman et al. (93) stated that inclusion of MUFA food sources in the diet may increase the compliance for a calorie-reduced diet during weight loss programs and promote weight-maintenance after a weight loss regimen. However, some studies have not shown a positive or negative association between BMI and MUFA intake (94,95) and specifically olive oil (96).

For the other unsaturated LCFA family, n-6 PUFA, Cunnane et al. (97) reported that -linolenate is the most oxidized 18-carbon chain PUFA, and arachidonic fatty acid is the least. Moreover, these authors stated that docosahexaenoate undergoes less -oxidation than do -linolenate or linoleate. When studying n-3 PUFA, Krebs et al. (26) have shown a weight reduction with the consumption of fish oil in humans. However, fish oil intake was combined with an energy-restricted regimen in this trial (26). In this study 35% of energy was derived from fat. A capsule of n-3 PUFA (1.3 g of eicosapentaenoic and 2.9 g of docosahexaenoic fatty acid) was given to the group that had been following the fish oil diet for 12 weeks. Couet et al. (98) also reported that with a consumption of daily fish oil (6 g/day) there was less fat deposition and an increase in the rate oxidation in non-obese subjects. In this last study, 32% of total energy was derived from fat.

Some data demonstrated that the P/S ratio in the diet affects the utilization of fatty acids in the diet. For instance, Clandinin et al. (99) found that on increasing the P/S ratio, a high oxidation rate was observed after consumption of both low- and high-fat diets (30 and 40% of energy coming from fat). These authors pointed out that since the intake of palmitic acid occurs from the upper third of the villus, increasing the P/S ratio in the diet seems to be associated with an increased rate of uptake of palmitic acid.

Recently, desaturases activity is being studied in association with obesity. Warensjo et al. (100) reported that BMI and waist circumference were positively correlated with increases in -6 and -9 desaturase activities and with elevated serum proportions of palmitic, palmitoleic, stearic, linolenic, and arachidonic acids. On the other hand, -5 activity and linoleic acid concentration in serum were inversely correlated with obesity markers. Their results suggest that a modification in the fatty acid profile in serum cholesteryl esters, which reflects to a certain extent the composition of dietary fatty acids and endogenous fatty acid synthesis, is correlated with desaturase activities and associated with obesity.

When observing Table 1, one can notice that clinical trials seem to have some conflicting outcomes. The main problem associated with these trials is uncontrolled conditions such as physical activity. Note that clinical trials in humans concerning the association between PUFA and especially fish oil intake and weight change are few.

Epidemiological Studies

In Table 2, we have summarized all epidemiological studies reported in literature. In this table we have included the purpose of the studies and their outcomes. The epidemiological studies addressing this issue are few. We identified eight cross-sectional and six cohort studies. We did not find any ecological or case/control studies. In this table, one can note that there are four cross-sectional studies, which reported a positive association between BMI and MUFA, SFA or PUFA (32,33,34,35). On the other hand, two studies have shown a negative association between BMI and the Mediterranean diet (101,102). It is interesting to note that two studies have not demonstrated any association between BMI and an increase in the intake of MUFA or olive oil (94,95). Williams et al. (34) showed a negative association between BMI and fish oil intake. Three cohort studies reported a positive association between BMI and MUFA or Mediterranean diet and SFA (36,37,38). Another cohort study has shown a negative relationship between BMI and the Mediterranean diet (103). On the other hand, two cohort studies have not demonstrated any association between BMI and oil olive intake (96,104). It is interesting to note that the purpose of these studies as observed in the table is not always to study primarily the association between weight change and type of fatty acids. From the 14 epidemiological studies, 9 studies had as their main objective to test for an association between weight change and the type of fatty acids; three studies reported a positive association between BMI and the type of fatty acid; three studies did not reveal any relationship between BMI and a high intake of olive oil, and the other three studies have shown a negative result for this association. These results are conflicting.

Table 2 - Epidemiological studies to determine whether fat composition is associated with change in body weight/body fat composition, rate oxidation, or energy expenditure.

Full table

In epidemiological studies, authors do not take into consideration physical activity, which is a major component of the energetic equation (105). At any rate, the measurement of intensity and duration in physical activity constitute a matter of conflict (105,106). Another problem in these types of studies is the adjustment of total energy intake (105,106) in populations. One can notice that when using several statistical methods for investigating the association between types of fatty acids in the diet and the prevalence of obesity different results may be achieved (105,106); one might acknowledge that total energy intake and the serving sizes reported are just estimated in most studies and may therefore impair the capacity of detecting an effect if present. There is also always the possibility of residual confounding factors which could in theory affect the observed association.

Conclusion

Although animal studies point to a possible association between the type of fatty acid consumed and obesity, and metabolic studies in humans follow that trend, the issue appears complex. In the nine epidemiological studies that directly examined the association between dietary fatty acid composition and body weight, the results have not been conclusive. In conclusion, given the potential public health implications of this question and the number of hypotheses that could be drawn about the consumption of different fatty acids and their association with obesity, there is an urgent need for conducting more studies—particularly case–control studies and analyses of large data sets (cross-sectional or longitudinal). Such studies were not feasible in the early 90s when the specific fatty acid content of numerous foods items was largely unavailable in food composition tables. Today these studies are certainly feasible.

DISCLOSURE

The authors declared no conflict of interest.

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