Eur J Nutr DOI 10.1007/s00394-013-0638-z

REVIEW

Effect of dietary fatty acid composition on substrate utilization and body weight maintenance in humans Sridevi Krishnan · Jamie A. Cooper

Received: 17 July 2013 / Accepted: 30 November 2013 © Springer-Verlag Berlin Heidelberg 2013

Abstract Background/purpose Dietary fat content is a primary factor associated with the increase in global obesity rates. There is a delay in achieving fat balance following exposure to a high-fat (HF) diet (≥ 40 % of total energy from fat) and fat balance is closely linked to energy balance. Exercise has been shown to improve this rate of adaptation to a HF diet. Recently, however, the role of dietary fatty acid composition on energy and macronutrient balance has come into question. Methods We chose studies that compared monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), and saturated fatty acids (SFA). We have reviewed studies that measured diet-induced thermogenesis (DIT), energy expenditure (EE), or fat oxidation (FOx) in response to a HF meal challenge, or long-term dietary intervention comparing these fatty acids. Results While single-meal studies show that SFA induce lower DIT and FOx compared to unsaturated fats, the effect of the degree of unsaturation (MUFA vs. PUFA) appears to yet be determined. Long-term dietary interventions also support the notion that unsaturated fats induce greater EE, DIT, and/or FOx versus SFA and that a high MUFA diet induces more weight loss compared to a high SFA diet. Sex and BMI status also affect the metabolic responses to different fatty acids; however, more research in these areas is warranted.

S. Krishnan · J. A. Cooper (&) Department of Nutrition, Hospitality, and Retailing, Texas Tech University, PO Box 41240, Lubbock, TX 79409, USA e-mail: [email protected] S. Krishnan e-mail: [email protected]

Conclusion SFA are likely more obesigenic than MUFA, and PUFA. The unsaturated fats appear to be more metabolically beneficial, specifically MUFA ≥ PUFA[SFA, as evidenced by the higher DIT and FOx following HF meals or diets. Keywords Fatty acids · Saturated fatty acids (SFA) · Monounsaturated fatty acids (MUFA) · Polyunsaturated fatty acids (PUFA) · Energy balance

Introduction Body weight and body fat regulation are influenced by both energy balance and macronutrient balance. Energy balance is the balance between energy intake and energy expenditure (EE), while macronutrient balance is the balance between macronutrient intake and subsequent macronutrient oxidation. The current obesity epidemic is a result of an imbalance in this equilibrium [15]. Both physical activity and diet play an integral role in energy and macronutrient balance [72]. Fats, carbohydrates, and proteins are the three primary dietary macronutrients that provide energy. In healthy adults, amino acid oxidation is usually matched by their dietary intake [64]. Between carbohydrates and fat, carbohydrate use regulates fat oxidation and storage according to the Flatt hypothesis [12]. This is primarily due to very low carbohydrate reserves in the body in the form of glycogen, compared to the much higher capability of the body to store fat in adipose depots. Hence, body fat maintenance is primarily dictated by the carbohydrate reservoirs in the body. According to the Flatt hypothesis, this reservoir, in conjunction with overall energy balance, controls fat balance. A high-fat (HF) diet (≥40 % of energy from fat sources) has been identified as one of the factors associated with the current obesity epidemic as it contributes to a positive

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energy balance and a short-term positive fat balance [73]. Due to the fact that fat oxidation does not match dietary intake on a per diem basis, and its storage capacity being large, long-term or frequent short-term impairment in fat balance has been considered a likely cause for obesity [64]. According to a review by Shutz [49], a dynamic fat balance equation taking into consideration the rate of change of energy intake and expenditure more appropriately represents weight balance. In the dynamic fat balance model, change in fat intake is considered over a function of time, and achievement of fat oxidation to match fat intake is defined as a function of percentage body fat. It also takes into consideration the fact that when an individual is in protein balance, their fat and carbohydrate balances are inversely related to each other. To date, a number of researchers have investigated the effect of (a) a single HF meal on acute metabolic responses, (b) metabolic adaptation across a few days (short-term HF diet response), and (c) intermediate or long-term metabolic adaptation occurring between a week up to a few weeks (long-term HF diet response). These studies point toward a direct impact on body fat gain with HF meals and/or diets and that these HF diets contribute to obesity [39, 48, 63]. These studies also suggest that body adiposity [3], physical activity, and glycogen stores [61], among other factors, play a role in altering the rate at which individuals adapt to a HF diet. Since fat balance is crucial to maintaining body weight, and achieving fat balance appears to be a complex phenomenon, the focus of this review paper will be to identify factors that influence a primary component of this balance—fat oxidation and EE. We will first summarize the literature on the metabolic adaptation process to a HF diet. For this section, we chose studies that have specifically investigated individual macronutrient—fat and carbohydrate balance as a function of a HF diet across time, in addition to showing evidence for how exercise affects this adaptation. Secondly, there is controversial literature with regard to the differential metabolic responses from HF diets due to varying fatty acids (FA) composition profiles of a HF meal or diet. In order to address this, we identified and summarized studies that have evaluated the effect of HF diets rich in individual FA on fat oxidation and EE. For reviewing acute feeding responses, we chose studies that used HF meal challenges and measured fat oxidation and EE either using labeled isotope tracers or indirect calorimetry. For intermediate and long-term diet responses, we chose studies that fed HF diets and reported fat oxidation, EE, and weight maintenance.

Intermittent positive fat balance from a HF diet In response to a HF diet, there is a delay in “adaptation” (change in substrate utilization based on macronutrient

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content in the diet) since fat oxidation does not match dietary fat intake (fat balance) immediately following the start of a HF diet. Schutz et al. [50] reported that fat oxidation did not match fat intake within 2 days of exposure to a HF diet, in seven healthy men. They also showed that energy balance was closely correlated with fat balance, but not with carbohydrate balance in these men. This indicates that fat imbalance can have a higher impact on energy balance than carbohydrate balance. Further exploring this concept, Schrauwen et al. [46] showed that it took 7 days for the body to achieve fat balance following exposure to a HF diet in 12 lean healthy men and women while in energy balance. Therefore, there is a period of positive fat balance for up to 7 days [46] during which fat intake exceeds oxidation, and Astrup et al. [2] indicated that this delay in adaptation to the HF diet can contribute to obesity. Factors that can influence the adaptation to a HF diet have been studied by researchers in the hopes of finding evidence linking it to obesity as well as ways to improve the adaptation process [5].

Exercise increases rate of adaptation to a HF diet To date, exercise appears to be the most effective means of increasing the rate of adaptation to a HF diet, and this has been shown in several studies as summarized in Table 1. Smith et al. [56] did a study on six healthy men who were fed a controlled diet for 5 days (with 37 % of energy as fat) following which they were switched to a HF diet (50 % energy as fat). Substrate oxidation and overall EE while on the HF diets were measured in a metabolic chamber, in addition to free living EE and VO2 max. The VO2 max in these individuals was the best predictor of fat balance while in a metabolic chamber and was also negatively associated with fat balance. This shows that the physical fitness of a person likely determines the rate at which fat balance is achieved following exposure to a HF diet. To add support to this, Schrauwen et al. [47] showed that glycogendepleting exercise prior to a HF meal challenge increased fat oxidation to the point of achieving fat balance, subsequent to intake, in 12 healthy non-obese men and women. When repeated in 10 healthy obese men and women, similar results were reported [45]. Further, Hansen et al. [14] tested the role of two different volumes of exercise (Physical activity level (PAL)—1.4 (sedentary), 1.6 (moderate volume) and 1.8 (high volume)) on the rate of adaptation to a high-fat diet in 10 non-obese women. They reported a graded increase in 24-h fat oxidation following the HF diet, corresponding to the increase in PAL, and concluded that fat balance could be achieved in as little as 4 days in conjunction with aerobic exercise. This was confirmed by Cooper et al. [8] in normal weight men. Thus,

Eur J Nutr Table 1 Exercise and adaptation to HF diets Authors

Year

Objective

Study design

Results—fat oxidation and energy expenditure

Smith et al. [56]

2000

How long does it take for adaptation to a HF diet to occur?

Intervention trial

6 healthy non-obese men were fed a controlled (37 % energy from fat) diet for 5 days, following which they were fed a HF diet (isoenergetic, 50 % energy from fat) for 4 days. They stayed in a metabolic chamber for measuring EE and substrate oxidation, and their free living EE and substrate oxidation were also measured prior to the HF diet. Their VO2 max was measured on a treadmill

Fat balance was not achieved within 4 days. Fat and carbohydrate balances were inversely correlated with each other. Stepwise regression model suggested that VO2 max was significantly associated with fat balance

Schrauwen et al. [46]

1997

Does glycogen lowering exercise increase adaptation to a HF diet?

Crossover design

12 non-obese men and women were fed a high-fat energy balance diets (60 % energy from fat) following glycogen lowering exercise (EX). Whole room calorimeter was used and control was no EX + HF diet. So: EX + HF versus no EX + HF

EX + HF matched their fat intake with oxidation (fat balance), however, the no EX + HF diet did not (positive fat balance)

Schrauwen et al. [45]

1998

Does exercise affect fat oxidation following a HF meal the same way in obese and normal weight individuals?

Crossover design

10 healthy obese men and women, 2 days of controlled RF diet (30 % of total energy as fat), followed by HF meal + glycogen lowering exercise (EX). They were tested in a whole room calorimeter for EE and Fat oxidation

Fat oxidation in HF + EX [ HF no EX leaning toward achieving fat balance

KC Hansen et al. [14]

2007

Does exercise increase adaptation to a HF diet?

Crossover design

10 adult non-obese women, fed a HF diet with sedentary and 2 volumes of exercise: PALs of 1.6 and 1.8

The higher PALs had a higher 24 h fat oxidation rate and lower NPRER. Fat balance achieved more quickly with exercise

JA Cooper et al. [8]

2010

Does FA composition and exercise affect adaptation to a HF diet?

Crossover design

8 non-obese sedentary men were given a MUFA-rich (30 % energy from MUFA) or SFA-rich (23 % of energy from SFA) diet for 5d, in addition to labeled 13C oleic acid and 2H palmitic acid during resting and exercise conditions. EE and fat oxidation were measured

Both diets showed higher EE (and lower NPRER) with exercise, compared to sedentary. There was no effect of the MUFA diet versus the SFA diet in fat oxidation and EE

PAL physical activity level, MUFA monounsaturated fatty acids, SFA saturated fatty acids, NPRER non-protein respiratory exchange ratio, EX exercise, HF high fat, RF reduced fat

it appears that acute bouts of exercise are capable of enhancing the rate of achieving fat balance which enables individuals to better tolerate HF meals by reducing the duration of positive fat balance. As mentioned above, achieving energy balance and macronutrient balance is crucial for the prevention of body fat and body weight gain. While exercise has been studied as a means of altering that adaptation process, in recent years, investigators have begun to study the composition of dietary FA within a HF meal or diet to explore the likely effect they have on adaptation to a HF diet, fat oxidation rates, and EE. In the Western diet, FA are predominantly long chain (≥13 carbons in chain length), with very few medium-chain (6–12 carbons in chain length) and short-

chain FA (\6 carbons in chain length) (Table 2). They can also be saturated fatty acids (SFA—no double bonds), monounsaturated fatty acids (MUFA—one double bond), or polyunsaturated fatty acids (PUFA—multiple double bonds). With regard to adaptation to a HF diet, Cooper et al. [8] studied the effect of FA composition and exercise for a 5day period in 8 healthy males. Subjects were fed either a MUFA- or SFA-rich HF diet and given labeled 13C oleic acid and 2H-labeled palmitic acid during both sedentary and aerobic exercise conditions. Irrespective of whether the diet was high in SFA or MUFA, exercise increased fat oxidation and led to a faster adaptation to a HF diet (fat balance was achieved more quickly). There was no effect

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123

≥C13 long and very long chain

C6–C12 Medium chain

3:0 4:0 5:0

Propionic acid

Butyric and Isobutyric acid

Valeric and Isovaleric acid

10:0 11:0 12:0

Pelargonic acid

Capric acid

Undecylic acid

Lauric acid

18:0 19:0

Margaric acid

Stearic acid

Nonadecylic acid

22:0 23:0 24:0 33:0

Behenic acid

Tricosylic acid

Lignoceric acid

Psyllic acid

20:0

17:0

Palmitic acid

21:0

16:0

Pentadecylic acid

Heneicosylic acid

15:0

Myristic acid

Arachidic acid

13:0 14:0

Tridecylic acid

Lauroleic acid Saturated

12:1

9:0

Caprylic acid

Unsaturated

6:0 8:0

Caproic acid

Saturated

1:0 2:0

Acetic acid

\C6 short chain

Length

Formic acid

Name

Chain length

–

–

–

–

–

–

–

–

–

–

–

–

–

n-7

–

–

–

–

–

–

–

–

–

–

–

Double bond

Chinese wolfberries

Peanut oil

–

Ben, rapeseed and peanut oil

–

Peanut and corn oil

Vegetable oils

Whole grains

–

Palm oil

–

Palm kernel and coconut oil

Food additives

–

Palm kernel and coconut oil

Castor oil

Palm, coconut

–

–

–

Food additives

–

Preservatives, food additives

Vinegar, food additives

Preservatives

Vegetable sources

Dietary sources

Table 2 List of fatty acids commonly (and some less commonly consumed) via dietary sources

–

–

–

–

–

–

–

Dairy and beef products

Dairy products

Dairy and mutton products

Dairy products

Dairy products

Sperm whale oil

–

–

Dairy products

Goat milk, dairy products

Fermented dairy foods

Butter, cream

Animal sources

Eur J Nutr

16:1

Palmitoleic acid

18:3 18:4 20:5 22:6

Alpha-linolenic acid (ALA)

Stearidonic acid (SDA)

Eicosapentaenoic acid (EPA)

Docosahexaenoic acid (DHA)

n-6

20:2 20:3 20:4 22:2 22:4 22:5

Eicosadienoic acid

Dihomo-gamma-linolenic acid Arachidonic acid (AA)

Docosadienoic acid

Adrenic acid

Docosapentaenoic acid

20:1 22:1 24:1

Elaidic acid

Eicosenoic acid

Erucic acid

Nervonic acid

n-9

n-9

n-9

n-9

n-9

n-6

n-6

n-6

n-6

Mustard, sesame, and macadamia nuts

Wallflower, rapeseed, kale, and mustard

Rape and mustard seed oils

Hydrogenated vegetable oils

Safflower, olive, rapeseed oils

–

–

Water melon seeds

Indirect sources—when converted from linoleic and alphalinolenic acid

–

–

Safflower, hemp, evening primrose oils

Safflower, sunflower, corn, wheat germ

–

–

Currants and Borage plants

Flaxseed, mustard, hemp seeds

Macadamia nut oil

Myristicaceae seed oil

Vegetable sources

Dietary sources

Dietary sources for fatty acids were identified from the USDA nutrient database, and when found, top 3 sources are listed

18:1 18:1

Oleic acid

ὠ—9

n-6

18:3

n-6

18:2

Gamma-linolenic acid (GLA)

n-6

n-3

n-3

n-3

n-3

n-3

n-7

n-5

Double bond

Linoleic acid

ὠ—6

16:3

Hexadecatrienoic acid (HTA)

ὠ—3

14:1

Unsaturated

≥C13 long and very long chain

Length

Myristoleic acid

Name

Chain length

Table 2 continued

Seafood—King and Sockeye salmon

Seafood—Atlantic Cod, Beluga, white whale blubber –

Goat milk, dairy products

Beef tallow, lard, and eggs

Seafood, fish, and eggs

Beef, pork, and eggs

Seafood—Clams and shells

Meat, seafood, poultry

Beef, chicken, and dairy fat

Pork, chicken, and turkey fat

Beef and pork fat

Pork, chicken, and turkey fat

Marine fish oils

Marine fish oils

Seafood—fish and seaweed

Sea buckthorn oil

Fat from seafood

Animal sources

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of dietary FA composition on total, endogenous, or exogenous fat oxidation, resting metabolic rate, or EE. However, there was a trend for greater total fat oxidation with the MUFA-rich versus SFA-rich HF diet [8]. They speculated that a longer time of exposure to the diets may have been required to see significant metabolic differences based on FA composition. As the WHO report on obesity suggests, the reduction in physical activity plays a primary role in the current obesity epidemic [71]. These studies show the positive effect of physical activity on fat balance while consuming HF diets, which is highly relevant given our predominantly sedentary lifestyle.

Acute response: dietary fatty acid composition effect on fat oxidation The question of whether or not the FA composition of a HF meal influences the process of adaptation to a HF diet and alters fuel substrate utilization has been addressed by few researchers [1]. Following HF exposure, researchers typically study substrate oxidation (especially respiratory exchange ratio (RER) and fat oxidation) and energy expenditure (EE) or diet-induced thermogenesis (DIT) to understand the metabolic responses to FA. Indirect calorimetry is the most commonly used technique to measure these parameters, but some researchers have also used stable isotope-labeled markers. We will summarize these studies here—categorized based on whether they employed indirect calorimetry or labeled isotopes.

Acute or single-meal studies using stable isotopes: effect on fat oxidation Dietary FA composition influences several metabolic responses, both acute postprandial responses, and chronic adaptations. Primarily, dietary FA composition influences the postprandial triglyceride composition in chylomicrons and VLDL, thereby determining what FA are available for oxidation. The rate of digestion and absorption affects which FA get packaged into chylomicrons and transported throughout the body. It is commonly known that short- and medium-chain FA, unsaturated FA, are absorbed faster than longer chain saturated FA immediately following a meal [40]. Furthermore, FA composition of prior meals will also account for changes in a subsequent meals’ postprandial fat oxidation. While labeled isotopes can provide accurate information about the metabolism of specific FA following a HF meal exposure, the abovementioned aspects need to be factored in while designing a study. Several researchers have used labeled isotopes to study fat metabolism. These studies are summarized in

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Table 3. Some of these acute feeding challenge studies reviewed here have monitored digestion and excretion of the fed FA in order to account for such differences [17, 40]. In addition, these studies also provided a standard diet for 3–5 days before the meal challenge test, to standardize the FA exposure prior to tests across all subjects [6, 8, 17, 40]. These controls enable better interpretation of the results from the following studies. One of the earliest studies was done by Jones et al. [19] where they looked at the degree of saturation of FA on oxidation. They did this study on six healthy male participants who were fed a HF diet (~40 % total energy as fat) for 2 weeks. Following this, they were fed a breakfast meal enriched with 13C-labeled stearic acid (18:0—SFA), 13C oleic acid (18:1—MUFA), and 13C linoleic acid (18:2— PUFA). Using breath collection (for isotope dose recovery), they measured exogenous fat oxidation. In addition, they measured fecal excretion of these labeled FA to account for dietary absorption. They identified that absorption of stearic acid was much lower than that of oleic and linoleic acid. Both oleic acid and linoleic acid had significantly higher oxidation rates compared to stearic acid when expressed as percentage of absorbed 13C which corrected for difference in absorption rates. Oleic acid had the highest oxidation rate among the three. Therefore, in this study, they showed that MUFA [ PUFA [ SFA for exogenous fat oxidation rates during HF feeding. Yet another study by Schmidt et al. [43] used 13C-labeled oleate or palmitate in a crossover study to measure differences in oxidation of these two FA. Ten healthy normal weight men were fed either labeled 13C-oleate or 13C-palmitate in a crossover manner with at least 3 days of washout between test days. They measured baseline and 8h postprandial 13C in breath samples and also measured 13C enrichment in plasma to account for differences in absorption of the FA. Oleate was oxidized 21 % more than palmitate, expressed as relative oxidation of what appeared in plasma chylomicrons following ingestion. Their conclusion was in agreement with Jones et al. [19] that MUFA is preferred over SFA as fuel. Other researchers have looked at the ratio of various FA in the diet. Clandinin et al. [7] studied six male volunteers in a crossover design testing 15 days of HF (40 % energy as fat)/high PS (PUFA:SFA::1:1), HF/low PS(PUFA: SFA::0.2:1), low fat(30 % energy as fat)/low PS or low fat/ high PS diets to identify whether a higher fat content, or differing FA composition, affected fat oxidation differently. They used labeled FA ranging from 13C10 to 13C16 (medium through long-chain FA) to identify their use as fuel. When subjects were on the high PS ratio diet, irrespective of total dietary fat percentage, oxidation of longerchain FA was significantly higher than in the lower PS ratio diet. The authors concluded that a higher PUFA content in

1985

1995

2000

1999

Jones et al. [18]

Clandinin et al. [7]

DeLany et al. [10]

Schmidt et al. [43]

Are palmitate and oleate differentially absorbed and oxidized?

Is there an effect of chain length and degree of unsaturation on fat oxidation?

Does the type of FA affect substrate use?

Is there a difference in the rate of individual fatty acid oxidation, either as a function of its absorption rate or just as a function of it being oxidized?

Objective

Crossover design

Crossover design

Crossover design

Crossover design

10 NW healthy men were fed either 13C palmitate or 13C oleate, and postprandial breath enrichment of 13C was measured to identify which FA was oxidized more

4 NW healthy men were fed a standard energy balance diet for 5 days. After 5 days, baseline breath samples were taken, following which they were given 13 C-labeled oleic acid (18:1, MUFA), palmitic acid (16:0, SFA), linoleic acid (18:2, PUFA), linolenic acid (18:3, PUFA), stearic acid (18:0, SFA), or lauric acid (12:0, SFA) in a random order. PP fat oxidation was measured

6 healthy NW men fed reduced fat (RF— 30 % of energy as fat) or HF (40 % of energy as fat) diet with high or low PS (PUFA:SFA) ratio with labeled 13C 10:0 (decaenoic acid) or 13C 16:0 (palmitic acid). PP substrate use was measured

6 NW healthy men were fed energy balance HF diet (40 % energy as fat) for 16 days. On days 8, 11, or 14, they were given labeled stearic (18:0, SFA), oleic (18:1, MUFA) or linoleic acid (18:2, PUFA) at breakfast. Breath and fecal excretion of 13C was measured for 9 h PP to evaluate preferential use

Study design

C Oleate was oxidized more than 13C palmitate during the 8 h PP period MUFA [ SFA

13

Fat oxidation: Medium chain [ long-chain FA among long-chain FA: PUFA [ MUFA [ SFA

Laurate [ linolenate [ elaidate [ oleate [ linoleate [ palmitate [ stearate. Laureate (medium-chain SFA) was oxidized more than long-chain unsaturated FA, and long-chain saturated FA like stearate and palmitate were oxidized lesser than PUFA and MUFA

Oxidation of long-chain MUFA/PUFA: high PS diet [ low PS

A high PS ratio HF diet induced greater increase in fat oxidation of long-chain unsaturated FA versus low PS ratio HF diet

Fat oxidation: MUFA [ PUFA [ SFA

Stearic acid was absorbed less than oleic acid and linoleic acid. Stearic acid was also the least oxidized, followed by linoleic acid, and oleic acid was the most oxidized based on 13C enrichment in breath samples PP

Results—fat oxidation and energy expenditure

PP postprandial, PUFA polyunsaturated fatty acids, SFA saturated fatty acids, MUFA monounsaturated fatty acids, NW normal weight, FA fatty acids, RF reduced fat

Year

Authors

Table 3 Acute or single-meal studies using stable isotopes—effect on fat oxidation

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the meals increased oxidation of long- and mediumchain PUFA and MUFA more so than SFA, so PUFA = MUFA [ SFA. Unfortunately, they did not incorporate any labeled FA of greater than 16 carbons in length. To further investigate whether chain length and degree of saturation of FA affects FA oxidation, DeLany et al. [10] measured the HF meal challenge response following a 1week HF diet (45 % carbohydrate, 15 % protein and 40 % of total energy as fat—42 % SFA, 36 % MUFA and 22 % PUFA) on fat oxidation in 4 healthy men. One week after the HF diet, subjects were given a HF liquid meal (similar composition as the diet) with either 13C-labeled lauric acid (12:0), palmitic acid (16:0), stearic acid (18:0), linoleic acid (18:1), linolenic acid (18:2), or linolenic acid (18:3). In the 9-h postprandial period following the liquid meal challenge, lauric acid (medium-chain SFA) was oxidized to the greatest extent, followed by linolenic (omega 3 PUFA), linoleic (omega 6 PUFA), oleic acid (MUFA), and finally palmitic and stearic acids (long-chain SFA). This indicates that if medium-chain SFA are present, they may be preferred as a fuel source, quite likely due to their easier absorption, and appearance in the plasma. For the longchain FA, greater exogenous oxidation was found with PUFA [ MUFA [ SFA. While this study did not measure fecal excretion of 13C, or measure plasma chylomicron enrichment of 13C, they used a hot blended FA meal that they indicated had ~95 % absorption of long-chain FA. To summarize the four studies, two compared PUFA versus SFA versus MUFA, and one compared SFA versus MUFA [10, 19, 43]. The fourth study investigated the effect of PS ratio on FA oxidation [7]. All three studies comparing SFA versus MUFA versus PUFA concluded that among long-chain FA, unsaturated fats (MUFA and PUFA) are oxidized to a greater extent than SFA, and specifically MUFA [ SFA [10, 19, 43]. While both Jones et al. [19] and Schmidt et al. [43] concluded that MUFA [ SFA for postprandial oxidation, DeLany et al. [10] was the only study that showed the opposite (PUFA [ MUFA). An advantage that both Jones et al. [19] and Schmidt et al. [43] have over DeLany et al. [10] is the fact that they measured fecal excretion or monitored appearance of FA in plasma chylomicrons to control for differences in absorption. Since it is known that the more unsaturated a fat is, the higher its degree of absorption [16, 18], their result PUFA [ MUFA for fat oxidation could likely be a function of the differences in absorption. Therefore, based on these studies, it can be inferred that MUFA and PUFA [ SFA is the preferred order for exogenous fat oxidation, with inadequate evidence to determine preference between MUFA and PUFA. The addition of indirect calorimetry studies that have compared the effect of PUFA versus MUFA versus SFA on EE and fat

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oxidation enables us to explore how different FA affect global fat oxidation and EE or DIT.

Meal challenge studies using indirect calorimetry: effect on fat oxidation, energy expenditure, and DIT Acute or single HF meal challenge studies measuring changes in EE or fat oxidation using indirect calorimetry have thus far revealed controversial results. While some researchers have observed that substituting SFA with MUFA increases postprandial fat oxidation [38], others have reported that SFA have the highest postprandial fat oxidation rates [29]. Five studies on a single-meal metabolic response to HF meals of varying FA composition have been published (Table 4). Piers et al. [38] reported that fat oxidation of a MUFA-rich HF meal (rich in olive oil) was much higher than a SFA-rich meal (cream) in the 5-h postprandial period in 14 normal weight, overweight, and obese males. They also reported a higher DIT following the MUFA- versus SFA-rich meals in individuals with high waist circumference (≥99 cm) compared to those with smaller waist circumferences. As a follow-up, Soares et al. [57] fed 12 postmenopausal women (4 normal/overweight, and 8 obese) the same contrasting meals (MUFA (olive oil) versus SFA (cream)—40 % of total daily energy needs as fat). They also observed that the MUFA-rich meal induced a higher DIT, in all their subjects and in the obese subset. They also found that fat oxidation was greater for the MUFA- versus SFA-rich meals, in all their subjects and in the obese subset as well. Finally, Jones et al. [17] compared a 60 % fat meal of olive oil, rich in oleic acid (MUFA), sunflower oil, rich in linoleic acid (omega-6 PUFA), or flaxseed oil, with a considerably higher linolenic acid:linoleic acid (omega-3:omega-6) ratio than sunflower oil in 15 normal weight healthy men. They showed that MUFA induced the highest postprandial EE, compared to omega-6 PUFA, followed by flaxseed oil (omega-3 PUFA); however, no differences in fat oxidation rates were observed. Contradictory to these findings, Flint et al. [13] tested three HF meals, rich in either MUFA, PUFA, and TRANS fats in 19 overweight men, and observed that there were no differences between the test meals in 5-h postprandial EE. Furthermore, Casas-Agustench et al. [6] studied 5-h postprandial EE from their crossover study comparing HF isocaloric meals comprising of PUFA (walnuts), MUFA (olive oil), or SFA (dairy) in nine healthy men. They reported that the high PUFA meal induced the highest postprandial DIT, followed by MUFA and least by the SFA-rich meal. The difference between PUFA and MUFA was not significant, while the SFA induced a significantly lower postprandial DIT than both PUFA and MUFA.

Eur J Nutr Table 4 Acute or single-meal studies using indirect calorimetry—effect on fat oxidation and energy expenditure Authors

Year

Objective

Study design

Piers et al. [38]

2002

Do HF (40 % of energy as fat) MUFA and SFA diets have different effects on PP fat oxidation or DIT?

Crossover design

Results—fat oxidation and energy expenditure 14 non-obese men were fed a HF MUFA or SFA diet to measure DIT and PP fat oxidation

High MUFA meal had a higher PP fat oxidation. DIT was also higher with the MUFA meal, but only in individuals with high waist circumference (≥ 99 cm) compared to those with lower waist circumference Fat oxidation: MUFA [ SFA DIT: MUFA [ SFA (in waist ≥ 99 cm only)

Flint et al. [13]

Soares et al. [57]

2003

2004

Does type of FA (MUFA vs. SFA vs. Trans FA) affect DIT?

Do MUFA and SFA have differential impact on PP DIT and fat oxidation rates?

Crossover design

Paired comparison

19 overweight, healthy men were fed HF breakfast meals (60 % of energy from fat) rich in either MUFA, SFA or trans FA (industrially prepared to make 95 % of the fat in each meal to match the required FA of choice). This was followed by 5-h PP EE measurement

No difference was found in DIT between the three types of HF meals

12 postmenopausal women were fed a high SF meal (high cream) or high MUFA meal (extra virgin olive oil), and DIT and EE were measured

DIT was higher following MUFA compared to SFA, and fat oxidation was also higher following the MUFA meal compared to the SFA meal, in the entire sample and in obese subset

DIT: MUFA = SFA = Trans FA

DIT and Fat oxidation: MUFA [ SFA in all subjects and in obese subset Jones et al. [17]

CasasAgustench et al. [6]

2008

2009

Does degree of unsaturation affect postprandial FA oxidation or DIT?

Does FA type affect PP oxidation or DIT?

Crossover design

Crossover design

15 healthy normal weight men were fed either—olive oil (oleic acid— MUFA)-, sunflower oil (linoleic acid—2nPUFA)- or flaxseed oil (linolenic acid—3nPUFA)-rich meals as part of breakfast. EE and fat oxidation were measured for 6h PP

Oleic acid had the highest DIT compared to linolenic, and a trend toward being higher than linoleic acid. No difference in fat oxidation rates was identified Fat oxidation: MUFA = PUFA

29 healthy, normal and overweight men were fed three isocaloric meals which were either rich in PUFA, MUFA, or SFA followed by 5-h PP measurements of EE and fat oxidation

There were no differences between meals in fat oxidation, while PUFA and MUFA meals were greater than SFA in DIT

DIT: MUFA [ PUFA

Fat oxidation: PUFA = MUFA = SFA DIT: PUFA and MUFA [ SFA, PUFA = MUFA

EE energy expenditure, DIT diet-induced thermogenesis, PP postprandial, MUFA monounsaturated fatty acids, SFA saturated fatty acids, PUFA polyunsaturated fatty acids, FA fatty acids

Similar to the results by Jones et al. [17], no differences in fat oxidation between the FA were observed. In summary, some of the acute meal challenge studies using indirect calorimetry showed differences between FA in DIT but not fat oxidation or vice versa. Of the four studies that measured fat oxidation [6, 17, 38, 57], two reported higher fat oxidation following a MUFA meal [38, 57], while the other two reported no differences between

FA [6, 17]. Further, Soares 2004 found differences in their obese subset of subjects, but did not test this in their normal weight/overweight subset, so it is difficult to conclude whether fat oxidation is influenced by adiposity. For DIT, 4 of the 5 studies reported differences based on FA composition. DIT was higher following the MUFA- versus SFArich meals in three studies [6, 38, 57] and greater than PUFA in one [17]. Two of these studies [38, 57] also found

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this difference specifically in their obese population. CasasAgustench et al. [6] did the only study comparing SFA, MUFA, and PUFA and reported both MUFA and PUFA to have greater DIT than SFA, but no difference between MUFA and PUFA. Together, the studies on DIT support that unsaturated fats (MUFA or PUFA) result in a greater DIT than SFA. The DIT response between MUFA versus PUFA remains to be determined. Combined with the fat oxidation data, the literature points toward the obesigenic effects of SFA versus both MUFA and PUFA. When considering both the stable isotope data and indirect calorimetry studies on fat oxidation, not all studies were in complete agreement. However, some conclusions can be drawn. Based on the stable isotope studies, exogenous fat oxidation is greatest for unsaturated FA PUFA and MUFA then followed by SFA [10, 19, 43]. Contradictory evidence between PUFA versus MUFA makes it unclear as to which one induces greater exogenous fat oxidation [10, 19]. Hence, more studies need to address this question. Total fat oxidation may not be different between dietary FA test meals acutely; however, in the studies where differences were found, MUFA led to more oxidation than SFA. Therefore, SFA appear to result in the lowest amount of fat oxidation (exogenous and total), while unsaturated fats, specifically MUFA, may lead to greater postprandial fat oxidation although more research is needed on the effects of total fat oxidation. As mentioned earlier, postprandial availability of FA is subject to digestion and absorption differences of FA and prior meal FA composition. Hence, acute meal challenge studies that measured systemic fat oxidation and EE used control measures that included a standard diet feeding protocol prior to testing. However, the following is an important limitation of shortterm feeding studies. Since MUFA are preferentially packaged and transported to be stored in muscle compared to SFA [70], their postprandial oxidation rates following a meal challenge will differ based on historical dietary fat consumption and prior body fat composition. Hence, while acute feeding studies can shed some light on postprandial fat oxidation, long-term dietary interventions that alter body fat and blood lipid composition to a larger degree will more accurately demonstrate the differential effect of altering dietary FA composition.

Intermediate and long-term high-fat diets: MUFA versus SFA While single-meal feeding responses provide important information about the acute influence of dietary FA on metabolism, long-term studies can provide a more comprehensive picture of the physiological effect of dietary FA composition on macronutrient balance, energy balance, and

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by extension, weight maintenance. Longer-term studies could also shed more light on the discrepancy between macronutrient balance and energy balance causing shifts in body weight. These studies are summarized in Table 5. Lovejoy et al. [29] examined the effects of MUFA, SFA, or Trans FA moderate fat diets (28 % of total energy from fat) on substrate oxidation over a 4-week period. Twentyfive healthy men and women were recruited to complete a 4-week controlled diet intervention in a crossover design, switching between a high MUFA diet (oleic acid), a high Trans FA diet (eladic acid), and a high SFA (palmitic acid) diet, with a 2-week washout period between treatments. MUFA, SFA, and Trans FA provided up to 9 % of total energy in the respective diets. They measured resting EE and substrate oxidation following each 4-week diet period in the fasted state and in an 8-h postprandial state after ingesting a diet-appropriate meal. The MUFA-rich diet had the lowest postprandial fat oxidation rate, followed by SFA, and the highest was for the Trans FA meal (Trans FA [ SFA [ MUFA). However, MUFA was only significantly lower than Trans FA and was not different from the SFA meal. Resting EE and DIT were not significantly different between the three diets. Thus, this study did not show differences between MUFA and SFA on energy or substrate metabolism. Contrastingly, Piers et al. [39] showed that high MUFA in the diet, compared to SFA can induce weight loss and body fat loss. They did a crossover study comparing a HF diet (40 % total energy as fat) with 24 % of total energy as SFA (high SFA diet) or 23 % total energy as MUFA (high MUFA diet). Eight overweight or obese men followed these diets for 4 weeks. The subjects were given all the food (in excess of their calculated needs) during the 4 weeks of their intervention, and they were asked to eat ad libitum. In addition to monitoring dietary intake, they also monitored physical activity using self-reported activity logs. Investigators reported that weight loss was three times higher in the high MUFA diet (−2.1 kg) compared to the high SFA diet (+0.5 kg) as was the reduction in fat mass (−1.1 kg for MUFA vs. +0.9 kg for SFA). They did not detect any differences in fasting or 5-h postprandial DIT or fat oxidation between the two diets. There were no differences in overall energy intake, fat or carbohydrate intake, or physical activity during the two diets. Therefore, while this study did not measure total EE, it can be speculated that total EE increased in the MUFA group, leading to the observed weight loss. This suggests a key role for MUFA in weight management, not to mention the potential detrimental effects of high SFA consumption on weight management. In support of this long-term beneficial effect of MUFA, Kien et al. [25] showed a higher calculated DEE with a high MUFA diet compared to a high SFA diet. Forty-three normal weight and overweight men and women were given

Year

2002

2003

2005

2007

Authors

Lovejoy et al. [29]

Piers et al. [39]

Kien et al. [25]

Kien and Bunn [22]

Does high palmitic or oleic acid in diet alter fasting and PP respiratory exchange ratio?

Would changes in oleic acid (MUFA) and palmitic acid (SFA) in the diet change DIT and fat oxidation?

Does a HF diet rich in either MUFA or SFA alter EE, fat oxidation or body weight?

Is there a difference between SFA (palmitic acid), MUFA (oleic acid) or trans FA (eladic acid) diets in PP substrate oxidation?

Objective

43 healthy men and women were placed on a HF diet rich in MUFA (78.4 % energy as MUFA) or SFA (40 % energy as SFA) for 28 days. After 28 days, fasting EE, PP EE, and fat oxidation were measured after a meal challenge using a meal with the same FA that they had been assigned to, in addition to calculating daily EE while on their respective diets using change in body weight and food intake

20 men and women were placed on a baseline diet (40 % as fat—with 13 % as MUFA and 8 % as SFA) for 28 days. On the 29th day, they were fed either a high MUFA (78 % total energy as MUFA, n = 11) or high SFA (40 %, n = 9) meal. EE, fat oxidation, and RER were measured in a respiratory chamber. They also calculated daily EE from the 28-day diets, similar to their earlier study in 2005

Doublemasked trial

8 obese or overweight men followed a MUFA-rich (22 % energy from MUFA) or SFA-rich (24 % total energy from SFA) HF (40 % total energy as fat) diet for 4 weeks. EE, Fat oxidation and body weight changes before and after the diets were recorded

25 healthy men and women were given 4 weeks of regular fat diet (28 % of total energy as fat) rich in MUFA, SFA, or trans FA (9 % of total energy in these forms). After each diet period, substrate oxidation and EE were measured using a breakfast meal of the same diet

Paired comparison trial

Crossover design

Crossover design

Study design

PP EE: MUFA = SFA Daily EE: MUFA = SFA

RER: MUFA = SFA

RER on the high MUFA diet was lower in the fed state compared to the high SFA diet. No differences in DEE or fat oxidation were observed

Daily EE: MUFA [ SFA

PP EE: MUFA = PUFA

PP fat oxidation: MUFA [ PUFA

Fasted fat oxidation: MUFA = PUFA

PP fat oxidation was significantly higher in the high MUFA diet than the high SFA diet, but no difference in fat oxidation were observed between diets in the fasted state. Estimated daily EE was higher in the MUFA group compared to the SFA group

Weight loss: MUFA [ SFA

No differential effects on fasting or PP EE or fat oxidation between the two diets. Weight loss at the end of the MUFA-rich diet was higher (-2.1 ± 0.4 kg) compared to SFA-rich diet (0.5 ± 0.9 kg). Body fat mass loss was also higher in MUFA-rich diet (−1.1 ± 0.7 %) compared to SFA-rich diet ( 0.9 ± 1.7 %) Fasting and PP EE and fat oxidation: MUFA = SFA

Trans FA [ MUFA, MUFA = SFA Fasting and PP EE and fasting fat oxidation: Trans FA = SFA = MUFA

PP Fat oxidation: Trans FA [ SFA

PP fat oxidation following the MUFA diet was lower than trans FA diet. SFA and MUFA were not different. No differences in DIT or overall TEE were found

Results—fat oxidation and energy expenditure

Table 5 Intermediate and long-term HF diets—effect on fat oxidation and energy expenditure comparing high MUFA versus high SFA

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FA fatty acids, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, HF high fat, DIT diet-induced thermogenesis, REE resting energy expenditure, RER respiratory exchange ratio, REE resting energy expenditure, PP postprandial

Physical activity: MUFA [ SFA (both cohorts)

REE: MUFA [ SFA (cohort 2) PP EE: MUFA [ SFA (cohort 1)

Physical activity was higher in the high MUFA diet compared to the high SFA diet. This study was unable to differentiate between the effect of higher physical activity or diet for the increase in REE and DIT

Resting EE was significantly higher after 3 weeks of the high MUFA diet, compared to the high SFA diet in cohort 2. DIT was higher in response to the MUFA diet and meal challenge in cohort 1, but not in cohort 2 Crossover design Is there a difference between high SFA (palmitic acid) and MUFA (Oleic acid) diet in REE and fat oxidation? 2013 Kien et al. [26]

Objective Year Authors

Table 5 continued

Study design

Study was done in two cohorts. Cohort 1 had healthy, non-obese, men and women (n = 18), and cohort 2 had both obese and non-obese subjects (n = 14). Both cohorts were given HF diets (40 % of total energy as fat), high SFA (40 % total fat energy as palmitic acid) or high MUFA (75 % total fat energy as oleic acid) diet for 3 weeks, with a 1-week washout between diets. On day 20 of each diet, a diet-appropriate meal challenge was given to measure resting EE and PP EE. Physical activity was measured during the intervention using accelerometers

Results—fat oxidation and energy expenditure

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a baseline HF diet (~15 % energy as protein, 45 % as carbohydrate and 40 % as fat—with 13 % as MUFA and 8 % as SFA) for 28 days. Following this, they were randomized into a SFA-rich diet (47.1 % of total fat energy as palmitic acid, n = 22) or a MUFA-rich diet (78.4 % of total fat energy as oleic acid, n = 21) provided at energy balance for 28 days. At the end of this 28-day period, they fed the volunteers a MUFA- or SFA-rich HF meal that corresponded to the diet they had been assigned to, to measure fasting and postprandial EE and fat oxidation. Fasting fat oxidation after the 28-day diets was not different between groups; however, the MUFA-rich meal challenge resulted in greater postprandial fat oxidation compared to the SFArich meal. There was a decrease in postprandial fat oxidation following the 40 % SFA diet, compared to the 40 % MUFA diet in the fed state. The investigators also calculated a weighted average daily RER and found that the decrease in RER for the high MUFA diet was different from the slight increase in RER for the high SFA diet. This pointed toward greater fat oxidation on a daily basis for MUFA- versus SFA-rich diets. For EE, there were no differences between the MUFA- versus SFA-rich meal challenges in fasted or postprandial states. In addition to this, they also calculated daily EE (DEE) for the duration of the 28 days intervention based on changes in body weight with a known amount of energy intake and observed that the DEE remained unchanged in the high MUFA diet, but decreased in the high SFA diet. Therefore, they concluded that EE is greater for a MUFA-rich compared to a SFA-rich HF diet. This study adds more support to the theory that SFA are less favorable and MUFA are more favorable, with respect to metabolism and weight maintenance. In another study, Kien and Bunn [22] repeated their earlier study using a sample of 20 men and women in a masked trial, 15 of whom were in the earlier trial in 2005 [29]. In this study, they measured EE and fat oxidation twice; once at the end of a 28-day baseline HF diet (~15 % energy as protein, 45 % as carbohydrate and 40 % as fat— with 13 % as MUFA and 8 % as SFA) for fasting EE and fat oxidation and again on the 29th day after being fed either a high SFA (n = 9) or high MUFA (n = 11) meal, in order to measure acute postprandial fat oxidation and EE responses. They reported no significant differences in EE in fed or fasted states, which confirmed their postprandial EE results from their previous study. No difference in RER or calculated DEE from the diets was reported, and the authors concluded it was due to insufficient power. One of the most recent studies by Kien et al. [26] compared a 3-week high MUFA (high oleic acid) to a 3-week high SFA diet (high palmitic acid) with a 1-week washout period between diets. Forty percent of total fat energy was SFA in the high SFA diet and 75 % of total fat energy was MUFA in the high MUFA diet. The study was done in two cohorts—with

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the first cohort using non-obese men and women (n = 9 each), and the second cohort 14 using obese and non-obese men and women (n = 7 each). After the 3-week intervention, the volunteers’ resting EE (REE) and postprandial EE following a high SFA or high MUFA meal (appropriate to their assigned intervention) were measured in a metabolic chamber. In addition, during days 2–21 and 2–18 for cohorts 1 and 2 during each intervention, accelerometers were used to measure physical activity. While cohort 1 had higher fasting REE in the high MUFA diet compared to the high SFA diet, cohort 2 had higher postprandial EE in the MUFA diet versus the SFA diet. Interestingly, physical activity, as measured by the accelerometer, was higher in the high MUFA diet in both cohorts compared to the high SFA diet. Therefore, the study was not able to differentiate between whether the higher physical activity or the FA composition of the diet was responsible for the observed changes in REE or postprandial EE and concluded that it was quite likely a combination of both. To summarize, the long-term dietary interventions by Kien et al. comparing MUFA versus SFA on calculated [25] or measured EE [26] indicated an increased REE, postprandial EE, or estimated daily EE for a MUFA diet compared to a SFA diet, although they did point out that a higher physical activity on the high MUFA diet might be part of the reason behind this. Their 28-day HF diet, followed by a high SFA or MUFA meal challenge test [22], however, showed that this long-term effect of high dietary MUFA may not be replicated in a single-meal challenge setting. On the other hand, both Piers et al. [39] and Lovejoy et al. [29] showed no differences between diets on DIT or EE. For fat oxidation, again Piers et al. [39] and Lovejoy et al. [29] found no difference between SFA and MUFA. Piers et al. [39] did report greater weight loss and body fat loss with the high MUFA diet compared to the SFA diet. Taken together, studies done by Piers et al. [39] and Kien et al. [25] support the notion that high MUFA diets might be metabolically beneficial to health. The results from Lovejoy et al. [29] should be compared to the other two with caution due to the fact that this study used a ~30 % of total energy as fat, with only ~9 % from MUFA or SFA, as opposed to Piers et al. [39] and Kien et al. [25], that used higher proportions of MUFA ([10 %) and higher proportions of fat % in their diets (≥40 % of total energy as fat). Finally, it must also be kept in mind that Kien et al. [25] used a calculated, not measured, DEE to look at the long-term effects on EE.

Intermediate and long-term high-fat diets: PUFA versus SFA While most of the studies previously discussed have been focused on comparing MUFA with SFA, some studies

looked at PUFA versus SFA, and they chose to do this by altering the dietary PUFA: SFA (PS) ratio (Table 6). Jones and Schoeller [21] compared a HF diet (45 % of total energy as fat) containing high or low PS ratio (1.65 ± 0.28 —high PS, and 0.241 ± 0.02—low PS ratios) in eight male volunteers. This was a crossover study design with no washout period between treatments. The volunteers were placed on these diets for 7 days, following which both fasting and postprandial EE and substrate oxidation were measured. The researchers found a significantly higher resting EE and postprandial fat oxidation following the high PS ratio diet compared to the low PS ratio diet. However, no difference in DIT was observed. In a longer-term intervention, Jones et al. [20] compared obese versus lean individuals, in addition to testing the response to a different PS ratio in the diet on fasting and postprandial EE and fat oxidation in a crossover design. Seven lean (four male, three female) and eight obese (four male and female each) healthy individuals were randomly placed on a 14-day high PS or low PS HF diet (45 % of total energy from fat). At the end of each 14-day intervention, there was a 7-day washout period with habitual diet before beginning the other diet. The PS ratio for the high PS was 1.13 in the lean and 0.91 in the obese subjects, and 0.26 and 0.28 for the low PS in the lean and obese subjects, respectively. On the 11th day and 14th day of each intervention, both fasting and post-breakfast EE and fat oxidation were measured. No differences were found in fasting fat oxidation between PS ratio diets or between obese versus lean groups. However, in postprandial fat oxidation, obese individuals showed lower fat oxidation following the low PS diet and meal challenge compared to high PS diet. Stated differently, having more PUFA led to greater fat oxidation. Importantly, this difference in fat oxidation between high PS and low PS was not found in the lean subjects. Additionally, the obese subjects had lower fat oxidation than lean subjects for the low PS but were not different than lean subjects for the high PS diet. These results suggested that body weight and adiposity might play a role in regulating substrate utilization with respect to different PS ratios. No significant differences were found between lean versus obese or between high versus low PS in resting of postprandial EE. This study indicates the likelihood of initial body weight regulating the impact of dietary FA composition on substrate utilization. Lichtenbelt WD et al. [67] in 1997 also conducted a 14day crossover dietary intervention comparing a HF (46 % of total energy from fat) high and low PS ratio (1.67 and 0.19, respectively), with a washout of 14 days between each diet in six healthy men. At the end of 14 days on the diets, both resting EE and DIT following a meal challenge with a similar PS ratio to the one they were assigned to was measured using indirect calorimeter. They found that the

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Eur J Nutr Table 6 Intermediate and long-term HF diets—effect on fat oxidation and energy expenditure comparing high PUFA versus high SFA Authors

Year

Objective

Study design

Jones and Schoeller [21]

1988

Do diets high in PS induce DIT and fat oxidation differentially compared to a low PS diet?

Crossover design

Jones et al. [20]

1992

Do high versus low PS diets influence fasting and PP EE and fat oxidation in lean and obese individuals differently?

Crossover design

Results—fat oxidation and energy expenditure 8 healthy men were randomly assigned to a HF diet (45 % of total energy as fat) diet for 7 days, with either a high PS ratio (1.65) or a low PS ratio (0.241) in a crossover design with no washout period. At the end of each dietary intervention phase (on day 7), fasting and PP EE and fat oxidation were measured using indirect calorimetry

Resting EE and PP fat oxidation was lower on the low PS diet compared to the high PS diet. DIT and fasting fat oxidation were not different between the two. REE: High PS [ Low PS

7 lean (4 male, 3 female) and 8 obese (4 male, 4 female) volunteers were placed on a HF diet (45 % of total energy from fat) with high or low PS ratio (high PS: 1.13, 0.91 and low PS: 0.26 and 0.28 for obese and lean, respectively) for 14 days, with a 7day washout between treatments. Fasting and PP EE and fat oxidation were measured

No difference in fasting and PP EE between lean versus obese or low versus high PS diet. PP fat oxidation was lower in the obese low PS diet compared to the high PS diet. PP Fat oxidation was also lower in the obese low PS diet compared to both the low and high PS treatments in lean individuals

PP fat oxidation: High PS [ low PS Fasting fat oxidation, High PS = low PS DIT: High PS = low PS

Fasting and PP EE: lean = obese, low PS = high PS Fasting fat oxidation: lean = obese, low PS = high PS PP fat oxidation: Obese: High PS [ Low PS Lean: High PS = Low PS Low PS: Obese \ lean High PS: Obese = lean

Lichtenbelt et al. [67]

1997

Do HF diets high or low PS ratio diets alter REE and DIT?

Crossover design

6 healthy men were placed on a HF (46 % of energy as fat) diet either with high PS ratio (1.67) or low PS ratio (0.19) for 14 days in a randomized order, with a 14-day washout between treatments. On the 14th day, both REE and DIT following a breakfast meal appropriate to the assigned diet were measured

Higher REE and DIT in the high PS ratio diet compared to the low PS ratio diet in 5 out of the 6 men REE: High PS [ low PS DIT: High PS [ low PS

FA fatty acids, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, HF high fat, DIT diet-induced thermogenesis, REE resting energy expenditure, RER respiratory exchange ratio, PP postprandial

high PS ratio had higher resting EE and DIT in 5 out of the 6 volunteers compared to the low PS ratio diet. This shows that PUFA induced EE and DIT more than SFA. To summarize the studies that have compared a high PUFA to a high SFA diet, Lichtenbelt et al. [67] is the only study among these three that shows that a high PUFA:SFA ratio is desirable for increasing DIT. Both Jones and Schoeller [21] and Jones et al. [20] show that a high versus low PUFA: SFA ratio did not differentially affect DIT. However, both these studies showed differences in fat oxidation as a result of different PUFA: SFA ratios. While Jones and Schoeller [21] identified this difference in

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postprandial fat oxidation, Jones et al. [20] only found this difference in obese individuals and not in normal/overweight individuals. This suggests that this difference between PUFA and SFA may be at least partially influenced by body weight and adiposity and that in lean individuals, there is a less pronounced difference in fat oxidation based on PS ratio. In addition, they identified no difference between lean and obese groups or as a result of the difference in PS ratios in fasting or postprandial EE (DIT). Also it is important to note that these studies do not mention the source of PUFA, such as omega-3 versus omega-6, or the types of omega-3s, such as alpha-linoleic

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acid, eicosapentaenoic acid, or docosahexaenoic acid. The dietary source for these would be relevant, especially while replicating these studies in future. Very few long-term HF feeding studies have been done comparing FA composition of diets, and there are inconsistencies in their comparisons either due to study design or methodology. Hence, more studies are needed to explore whether MUFA, SFA, or PUFA are preferable with respect to DIT, EE, fat oxidation, and adaptation to HF diets. More importantly, long-term HF feeding studies should measure and report fat balance at the beginning and end of the intervention, in addition to reporting on EE and substrate oxidation, in order to truly understand whether differences in FA composition affects adaptation to a HF diet.

High-fat meals or diets: difference based on BMI status While HF meals may not depict true long-term dietary habits, studies looking at a standard Western diet (50 % carbohydrate, 35 % fat and 15 % protein) that measured substrate utilization have shown that fat oxidation is lower in obese individuals compared to their leaner counterparts [55]. Several earlier studies by Segal KR et al. [53, 54] also indicated a reduced thermic response to HF or fat-rich meals in obese compared to normal weight or lean men. Furthermore, Westerterp KP et al. [71] reported a significant negative association between 12-h postprandial dietary fat oxidation (measures using stable isotopes and indirect calorimetry) and both BMI and total body fat percentage. This was found in a subject population of 18 men and 38 women. Conversely, in 2008, Tentolouris et al. [66] reported that in women, there were no significant differences in DIT to a fat-rich meal (~88 % energy as fat) irrespective of BMI status. Following up on this, in 2011 Tentolouris et al. [65] reported no differences between 19 lean and 22 obese women in the DIT of a fat-rich meal (~88 % energy as fat). Neither of these studies, however, looked at the effects of FA composition. In summary, according to these studies, lean and obese individuals display different DIT and fat oxidation responses to HF meals (with nonspecific FA composition), with the exception of results from Tentolouris et al. in 2008 and 2011. The next logical question is whether or not dietary FA composition in HF meals also plays a role in DIT and fat oxidation response differences between normal weight and obese individuals. Only two of the studies included in this review measuring metabolic responses to dietary FA composition in a single meal actually looked at the influence of weight, body fat, or BMI status [6, 57]. Further, only one long-term dietary intervention study with differing FA composition compared lean and obese individuals [20]. Moreover, while all the studies reviewed under the

heavy isotope label section used normal weight men, among the studies that used indirect calorimetry, Piers et al. [38], Flint et al. [13], and Casas-Agustench [6] studied overweight men along with normal weight men. Jones et al. [17] studied only normal weight men, and Soares et al. [57] studied normal weight, overweight, and obese women. No study has looked at the acute meal challenge response in obese men. Piers et al. [38] reported a higher DIT in men with higher waist circumference on a high MUFA diet compared to ones with lower waist circumference (\99 cm). Soares et al. [57] showed a higher fat oxidation following a high MUFA meal, compared to a high SFA meal in obese, but did not report on just their overweight or normal weight postmenopausal women sample. Other studies, such as that done by Flint et al. [13], had an overweight male population, but they did not compare this to normal weight subjects. Jones et al. [20] was the only long-term study to compare obese versus lean individuals in a high versus low PS diet and showed that obese individuals had a lower fat oxidation following low PS diet compared to high PS diet, but that this difference was not found in lean individuals. However, this study looked at different PS ratios in different BMI populations and compared PUFA versus SFA, not MUFA versus PUFA versus SFA, which would have been more comprehensive. Due to the lack of comparisons between normal weight, overweight, and obese subjects, it is difficult to infer whether any metabolic differences in response to FA composition exist. Based on the two studies that have examined the role of weight status, FA composition may influence metabolic responses (DIT and/or fat oxidation) in overweight or obese individuals more so than in normal weight individuals, which is important information for understanding body weight regulation. However, whether or not there is a difference between PUFA and either MUFA or SFA is still unclear because only one study [6] compared PUFA versus MUFA versus SFA in overweight and normal weight individuals.

High-fat meals or diets: difference based on sex As noted in our prior discussion, very few investigators have looked at the role of sex on metabolic responses to dietary FA. This is surprising given that the sex steroid hormones, estradiol and testosterone, differentially regulate both body adiposity and lipolysis [4]. Further, the majority of the acute feeding studies discussed in this review using indirect calorimetry or stable isotopes were carried out in men. Kien and Bunn [23] were the only investigators to look at sex differences in their 28-day feeding study in 43 adults (22 females and 21 males—Table 5). Subjects were fed a high MUFA or high SFA diet for 4 weeks followed

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by a high MUFA or SFA meal challenge. Fat oxidation and EE were measured in the fasted and fed states, and DEE was also calculated. They concluded that postprandial fat oxidation and overall (fasting postprandial) EE had increased in women on the high MUFA diet and decreased for the high SFA diet. They also showed an increase in DEE on high MUFA diet, compared to high SFA diet. Conversely, in men, there were no significant differences in fat oxidation based on FA composition of the diets, but EE increased on the high MUFA diet compared to the high SFA diet. Therefore, it appears that a sex difference exists in response to dietary FA composition and adaptation to different HF diets. Based on their study, FA composition may influence metabolic responses in women more so than in men, which is important information for body weight regulation. To our knowledge, this is the only study that reported differences between the two sexes in response to either a single HF meal challenge or HF diet with differing FA composition. Hence, more research in this area is warranted.

Impact of the chain length of fatty acids on metabolism Similar to the question of whether the degree of unsaturation of the FA plays a role in its rate of oxidation, it is also of interest to identify whether the chain length of a FA plays a role in substrate oxidation. Two of the studies previously mentioned, DeLaney et al. [10] and Jones et al. [19] also evaluated whether chain length affects oxidation. Both identified that medium-chain FA (such as lauric acid) were oxidized before longer-chain (palmitic and stearic) FA. They also identified that this preference for the shorter chain length FA being oxidized sooner than longer-chain FA was particularly true with SFA (lauric vs. palmitic vs. stearic), but not in unsaturated FA. Also, medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) have been tested in intervention trials and provide further support that postprandial EE [33, 52, 60] and fat oxidation [42, 58, 59] following MCTs are higher than LCTs [60]. MCTs were also more helpful with body weight and adiposity loss [41, 60]. Hence, it appears that medium-chain FA are preferable over long-chain FA with respect to thermic effect/postprandial EE and fat oxidation, and overall body weight and body fat maintenance or even loss.

High-fat meals, energy balance, and insulin sensitivity Both energy balance and macronutrient balance are important regulators of body weight status in humans. However, dietary FA composition in a HF meal or diet impacts more than just metabolism. One other important

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marker is insulin sensitivity. Higher dietary fat intake and higher circulating plasma-free FA are implicated in the onset of insulin resistance [30, 44]. Of particular relevance to this review are studies that have looked at whether the composition of dietary FA in HF meals or diets affects insulin sensitivity/resistance. Several cross-sectional epidemiological studies have been done investigating the relationship between dietary FA composition and markers of insulin sensitivity in healthy individuals. Some earlier studies [31, 34–36] did not identify differences between SFA and MUFA/PUFA intake on insulin sensitivity and reported no associations between dietary FA composition and insulin sensitivity. Conversely, others [32, 37] identified inverse associations between SFA intake and insulin sensitivity. One such study by Corpeleijn et al. [9] recently identified an inverse association between SFA intake and insulin sensitivity, in addition to a positive association between MUFA/PUFA and insulin sensitivity. It is crucial to bear in mind that these epidemiological studies used primarily fasting measures of insulin to classify individuals as hyperinsulinemic and identify associations with dietary FA composition, if any. Further, they used food records, food frequency questionnaires, or food diaries to obtain information pertaining to dietary FA composition. Hence, there is reporter bias involved that makes these results more questionable than randomized controlled intervention studies. Therefore, diet intervention studies may be more pertinent. Several earlier dietary intervention studies identified no difference in insulin sensitivity between diets rich in SFA versus MUFA [11, 27, 51], PUFA versus MUFA [28], or all three [29, 62]. A larger randomized intervention trial comparing high SFA versus high MUFA diets (38 % total energy from fat, SFA:MUFA:PUFA—16:12:6 % vs. SFA: MUFA:PUFA—8:20:6 %) supported the earlier conclusions from interventions that saturation of fats, SFA versus MUFA specifically, does not impact insulin sensitivity. However, contradictory to these earlier findings, Vessby et al. [68] (compared SFA vs. MUFA) and Summers et al. [69] (compared PUFA vs. SFA) identified a reduction in insulin sensitivity following 4 weeks of the HF SFA-rich diet compared to either unsaturated FA diet. Additionally, a recent HF SFA versus MUFA intervention trial by Kien et al. [24] also showed that replacing SFA with MUFA resulted in improvements in insulin sensitivity. Of importance to note is that the study by Summers et al. [71] had obese and type 2 diabetic individuals, rather than the healthy individuals used in the other studies. Based on the dietary intervention studies, it appears that while earlier studies found no differences on insulin sensitivity, more recent evidence indicates a preference for MUFA over SFA for improved insulin sensitivity. Further, even though

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epidemiological studies used lesser sophisticated tools for evaluating this relationship, there is evidence to support higher intake of MUFA over SFA as well. While both PUFA and MUFA appear to be better than SFA, more studies need to evaluate the effect of PUFA versus MUFA to identify their impact as well.

rich diet, it appears a high medium-chain FA-rich diet is favorable in increasing postprandial energy expenditure, and fat oxidation, thereby promoting body weight maintenance and fat balance.

Limitations Conclusion The transient delay in adaptation to a HF diet has been linked to obesity. However, this delay has been shown to be reduced by exercise. Another aspect that likely influences this delay is the FA composition in the diet. While most studies appear to indicate that higher MUFA content in the diet increases fat oxidation and EE, a few other studies contradict this notion. The labeled isotope studies indicate that, MUFA ≥ PUFA [ SFA is the preferred order for oxidation in the body. However, the HF meal challenge studies showed that the difference in FA composition affects EE, DIT, and fat oxidation differently. A high MUFA meal or diet may lead to greater fat oxidation compared to a high SFA diet. About half of the studies support this conclusion, while the other half do not seem to find any differences in fat oxidation based on FA composition of a meal or diet. A high MUFA diet increases DIT more so than a high SFA diet, and this effect is enhanced in obese individuals more than in normal weight or overweight subjects. Furthermore, a meal high in PUFA: SFA ratio also increases fat oxidation compared to a low PUFA: SFA ratio, suggesting that PUFA is beneficial in inducing fat oxidation more than SFA. Finally, fat oxidation and DIT responses to HF meals or diets of varying FA composition may be affected by BMI status or sex of the participants. Overweight and obese women responded with a higher DIT and fat oxidation following a high MUFA diet, compared to high SFA diet while men did not. Also, a high PUFA: SFA ratio induced fat oxidation in lean subjects more than a low PUFA: SFA ratio, indicating the detrimental role high SFA diets might play in pre-existing high adiposity. These imply that factors such as body weight and gender play an important role in understanding metabolic responses to different diets or meals and can influence the clinical application of this information for weight maintenance. In conclusion, a high MUFA or PUFA diet appears to be more metabolically beneficial compared to a high SFA diet in terms of EE and weight maintenance. There is more evidence to support a high MUFA versus SFA diet rather than a high PUFA versus MUFA or SFA diet, in maintaining body weight, energy balance, and insulin sensitivity based on the isotope-labeled studies and the human feeding studies we have reviewed here. While considering a high medium-chain versus long-chain FA-

In reviewing all of the literature on the impact of FA on metabolism, some limitations became apparent. For the stable isotope-labeled studies, no EE or DIT information is available. This limits the findings of these studies as it relates to energy balance. For the HF diet or meal challenge studies, several limitations in being able to accurately compare one study to another were found. Participant populations varied greatly and the study designs were different. The major differences include the total amount of fat in a meal or diet (ranged from 26 to 60 %), the number of FA studied (many studies looked at MUFA and SFA while few included PUFA-rich diets or meals), and the amount or percentage of MUFA, PUFA, and SFA in each meal or diet. For example, a MUFA-rich diet may have had 80 % of fat energy from MUFA, while a SFA-rich diet may have had 40 % of fat energy from SFA. This is a common limitation to these types of studies; however, it makes comparing one study to another quite difficult since most studies end up having a different percentage of total energy as MUFA, PUFA, and SFA. Additionally, long-term diet intervention studies looking at weight management with MUFA- or SFA-rich diets have shown that MUFA-rich diets help weight loss, but have failed to measure EE, and only reported calculated EE. Finally, to study energy balance and weight maintenance, it is important to look at both energy intake and energy expenditure. In this review, we focused on macronutrient balance and energy expenditure; however, we did not examine how dietary FA may affect energy intake. The impact of certain high-fat diets on long-term energy intake may play an important role in body weight and body fat maintenance.

Future direction The conflicting results for metabolic responses to different FA in meal challenge studies indicate a need for more research in this area. Several studies have found significant differences, so it is likely that metabolic differences exist. However, the exact meal composition or study population necessary to detect those differences remains to be determined. Future studies also need to include PUFA-rich meals or diets in addition to studying MUFA- and SFA-rich meals or diets. Additionally, differences in the metabolic responses to different FA between men and women as well

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as individuals of different BMI status need to be explored. Finally, the lack of a comprehensive study looking at measured EE in response to a controlled, randomized longterm MUFA, PUFA, and SFA diet intervention with adequate washover period to compare DIT and EE responses is one of the reasons, and there is no clear answer to whether different FA compositions in diets affect adaptation to a HF diet and weight and body fat maintenance. Until such a study exists, it is difficult to draw conclusions on the longterm metabolic consequences of consuming diets rich in different FA.

12. 13.

14.

15. 16.

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

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