Using food and food components to control lipogenesis and thermogenesis

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In this section, foods and food components that have the potential to assist weight loss/maintenance due to effects on lipogenesis, thermogenesis and/ or body composition are presented.

4.5.1 Dietary fats

Dietary fat is related to the etiology of obesity because of its high energy density, high hedonic value, delayed satiating capacity thus promoting passive overconsumption, low associated thermic effect and efficient storage capacity. This has fueled the market for low-fat and fat-free foods for weight management. However, there is evidence that not all fats are equally bad.81 Some specific fats and fat types, when consumed in replacement of other, less convenient, fats, may help prevent body weight gain, or may even enhance body weight loss in the context of more rigorous weight-loss plans. These fats are presented below.

Polyunsaturated fatty acids

For many years it has been known that PUFAs have a certain capacity of lowering adiposity and plasma triacylglycerol levels, mainly due to their effects of inhibiting lipogenic capacity and activating fatty acid catabolism in the liver (reviewed in references 82-84; see also Chapter 13).

In the liver, PUFAs repress the expression of the key lipogenic transcription factor SREBP-1 (by binding to and blocking the activity of a transcription factor, liver X receptor, needed for efficient SREBP-1 gene transcription) and inhibit the proteolytic process leading to SREBP-1 activation (reviewed in references 82-84) (Fig. 4.4). PUFAs also inhibit, by a post-transcriptional mechanism, the hepatic expression of glucose-6-phosphate-dehydrogenase, a key enzyme in the pentose phosphate pathway,85 thus compromising NADPH availability for de novo fatty acid synthesis. On the other hand, PUFAs and PUFA-derivatives enhance fatty acid oxidation and fatty acid oxidation capacity in the liver. This enhancement is achieved through: (1) suppression of the expression of the lipogenic enzyme acetyl-CoA carboxyl-ase (ACC) and subsequent reduction of the hepatic levels of its product, malonyl-CoA (which is both a substrate in fatty acid syntheis and a powerful inhibitor of fatty acyl-CoA uptake by mitochondria, the rate-limiting step in mitochondrial fatty acid oxidation); and (2) through activation of PPARa, a lipid-activated transcription factor abundantly expressed in hepatocytes that up-regulates the expression of a collection of genes for proteins involved in mitochondrial, peroxisomal and microsomal fatty acid catabolism (reviewed in reference 83).

PUFAs also have potential anti-adiposity effects targeting tissues other than the liver, such as WAT and muscle. Dietary n-3 PUFAs were shown to depress lipogenesis and down-regulate the expression levels of a collection of lipogenic genes, to up-regulate mitochondrial biogenesis and to induce beta-oxidation of fatty acids in visceral WAT depots of rodents.8687 PUFA may also enhance fatty acid oxidation in muscle,88 although the effect appears to be less marked than in the liver (reviewed in reference 83). PUFA-induced increases in fatty acid oxidation may be linked to increased thermo-genesis, since PUFAs were shown to up-regulate the expression of uncoupling proteins, including UCP1 in BAT,89 UCP3 in skeletal muscle88 and UCP2 in liver and WAT.9091 Both the UCP1 gene and the UCP3 gene contain a PPAR response element in their promoter, which may explain their sensitivity to PUFAs (PPARs are activated as transcription factors after binding certain fatty acids or fatty acid derivatives) (see reference 73).

Biological activities of n-3 and n-6 PUFAs

PUFAs active in the regulation of gene expression and lipid metabolism are highly unsaturated fatty acids of 20 and 22 carbons of both the n-3 and the n-6 series, such as arachidonic acid (20 : 4, n-6), docosahexaenoic acid (DHA, 22 : 6, n-3) and eicosapentaenoic acid (EPA, 20 : 5, n-3). These fatty acids can be produced endogenously from linoleic acid (18 : 2, n-6), which is the precursor of arachidonic acid, and linolenic acid (18 : 3, n-3), which is the precursor of EPA and DHA, through the action of delta-5 and delta-6 desaturases. Linolenic acid is present predominantly in flaxseed, soybean and canola oils, and in English walnuts. Linoleic acid is found in most vegetable oils (such as corn oil and sunflower oil) and most nuts. However, only small amounts of linoleic and linolenic acids undergo delta-desaturation in the body. Therefore, foods rich in fatty acids that are the products of delta-desaturases, that bypass the regulated and required steps of further desaturation and elongation, are much more effective suppressors of hepatic lipogenesis and inducers of fatty acid oxidation than are foods rich in lin-oleic acid or linolenic acid, the substrates of delta-desaturases.3 This is the case of fish oils, which are rich in long-chain highly polyunsaturated fatty acids of the n-3 series (DHA and EPA).

In other aspects, PUFAs of the n-3 and the n-6 series appear to have different biological activities. For instance, n-6 PUFAs have a greater hypo-cholesterolemic effect than n-3 PUFAs,92 while n-3 PUFAs, due to the particular eicosanoids to which they give rise, appear to have beneficial effects on vascular endothelial function that are not displayed by the n-6 PUFAs, from which a different set of eicosanoids is produced (reviewed in reference 93). Together with their marked hypotriglycerydemic effect, this may explain the reduced risk of cardiovascular disease associated with fish and fish oil consumption that has been repeatedly observed in human epidemiologic studies and clinical intervention trials (reviewed in references 92 and 94).

PUFAs of the n-6 and n-3 series also differ in their effects on adipogene-sis. Linoleic acid and arachidonic acid (both n-6 PUFAs) may be particularly pro-adipogenic, because they serve as precursors in pre-adipocytes of prostacyclins which, in a paracrine/autocrine fashion, through activation of a specific cell surface receptor, trigger early adipogenic events in these cells (reviewed in reference 95). Interestingly, n-3 PUF As inhibit the above process, and in this sense can be considered as anti-adipogenic.95 It has been suggested that a high dietary n-6 PUFA/n-3 PUFA ratio during early life and infancy may favor increased adipocyte numbers and future obesity, and it is remarkable that this ratio has continuously and markedly increased in human breast milk over recent decades.95

Studies in rodents have consistently reported that intake of n-3 PUFAs reduces adipose mass, preferentially visceral fat, in general without affecting body weight (see references in reference 87). Some studies in humans also reported an effect of dietary fish oil consumption increasing whole-body lipid oxidation and decreasing total body fat content,96 and specifically abdominal fat content.97 Most human studies, however, have so far examined the effect of PUFA intake on end-points related to cardiovascular health and insulin sensitivity, rather than to body weight and body fat control. There is a paucity of human studies specifically designed to ascertain whether the intake of PUFAs (or PUFA-rich foods such as fish oils and nuts) can assist in weight loss and/or in weight maintenance after weight loss in the long-term.

Monounsaturated fatty acids

Monounsaturated fatty acids (MUFAs), and particularly oleic acid, appear to have beneficial effects regarding cardiovascular health and insulin sensitivity (reviewed in references 98 and 99). MUFAs may also be beneficial in the context of weight-management strategies. For instance, MUFAs induce a lower increase of postprandial triglyceridemia than saturated fats100 and may favor energy expenditure and thermogenic function. In a rodent study in which the influence of four dietary lipid sources (olive oil, sunflower oil, palm oil and beef tallow) were compared, it was found that total-body oxygen consumption was higher in rats fed olive oil than in those fed the other three diets, and that olive oil feeding induced the highest uncoupling protein expression in BAT and skeletal muscle.101

These and other results have prompted considerable interest in the use of modified fat diets rich in MUFAs for weight management. To date, however, there is no evidence from ad libitum dietary intervention studies that a normal-fat, high-MUFA diet is similar to a low-fat diet in preventing weight gain.102 Likewise, there is no evidence that energy-restricted, moderate-fat diets rich in MUFAs are better than isoenergetic diets with mixed dietary fats103 or a low fat content104 105 for weight loss, although in some studies the MUFA-rich diets did improve the cardiovascular disease risk profile relative to the low-fat diets.105,106

Medium-chain triacylglycerols

Medium-chain triacylglycerols (MCTs) are triacylglycerols composed of fatty acids that contain 6-12 carbon atoms (see also Chapter 14). Medium-

chain fatty acids (MCFAs) formed upon digestion of MCTs behave in a metabolically different way to long-chain fatty acids (LCFAs, of more than 12 carbon atoms) derived from long-chain tricylglycerols (LCTs). LCFAs require chylomicron formation for their absorption and transport. MCFAs, in contrast, are transported in the portal blood directly to the liver, thus bypassing peripheral tissues such as adipose tissue, making them less susceptible to the action of LPL and to deposition into adipose tissue stores. The structure-based differences continue through the processes of fat utilization: thus, unlike LCFAs, MCFAs enter the mitochondria independently of the carnitine transport system, so that they may be more easily oxidized.107

Studies in animals and humans have shown that MCTs have a greater thermogenic effect than LCTs in the short term, probably due to their rapid oxidation (reviewed in reference 108). Longer studies in animals and humans have shown that consumption of MCTs instead of LCTs can result in less body weight gain and decreased size of fat depots.108-110 Coconut oil is particularly rich in MCTs, and we found in rats that a coconut-oil enriched diet was particularly effective in stimulating BAT UCP1 expression during ad libitum feeding and in preventing UCP1 down-regulation during food restriction, and that these effects went hand in hand with a decrease in the mass of white fat stores.111 Furthermore, data suggest that MCT consumption increases satiety more than LCT consumption.108109

The above results indicate the potential for MCTs to act as dietary adjuncts for improved body weight maintenance or even possibly weight loss. However, evidence for the latter role is not compelling from the human studies conducted so far. In one study, hypocaloric feeding in obese women with a diet containing 24% of calories as MCTs did not result in increased rate or amount of weight loss (compared with LCTs) after 12 weeks.112 In another study, MCTs as part of a very low calorie diet supported higher weight and fat loss than LCTs during the first two weeks, accompanied by less intense hunger feelings and increased satiety, but the effects gradually declined during the third and fourth weeks of treatment, indicating subsequent metabolic adaptation.113 In addition, there are some concerns regarding the cardiovascular effects of MCTs, because MCT consumption was found to result in increased total cholesterol, LDL-cho-lesterol, triacylglycerol and glucose concentrations in plasma.114 MCTs appear to increase hepatic de novo lipogenesis and to enhance insulin sen-sitivity.112115 Thus, findings in support of a potential slimming effect of MCTs (lower energy density, control of satiety, rapid intrahepatic delivery and oxidation rates, poor adipose tissue incorporation) may be invalidated by counteracting effects (stimulation of insulin secretion and of anabolic-related processes, increased de novo fatty acid synthesis and induced hypertriglyceridemia).116


Substitution of triacylglycerols in the diet by diacylglycerols has also been proposed to be of potential value in the prevention and management of obesity, probably because of effects of diacylglycerols that are similar to those of MCTs. Whereas triacylglycerols are catabolized to two fatty acid molecules and a 2-monoacylglycerol molecule that in the enterocyte acts as a backbone for the reformation of triacylglycerol molecules for packaging into chylomicrons, diacylglycerols of the 1,3 conformation are catabolized to two fatty acids and a glycerol moiety, which may be diverted through the portal circulation directly to the liver. Thus, fatty acids derived from diac-ylglycerol may be less available to adipose tissue and more easily oxidized in the liver.

Reported effects of the intake of diacylglycerol compared with triacyl-glycerol of a similar fatty acid composition include, in animals, lowering of plasma triacylglycerol levels and decreasing postprandial hyperlipidemia, increasing energy expenditure, increasing lipid oxidation capacity in liver and intestinal cells, and reducing diet-induced obesity117118 (reviewed in reference 119). The serum triglyceride-lowering effect of diacylglycerol compared with triacylglycerol intake can be related to an impairment of chylomicron assembly and subsequent release into the blood through the lymph, because reacylation to triacylglycerol in small intestinal cells was found to be slower with diacylglycerol feeding than triacylglycerol feeding.119 Stimulation of enzyme activities responsible for beta-oxidation in the small intestine and liver may also contribute to reduced postprandial hyperlipid-emia as well as to increased energy expenditure, which result in suppression of diet-induced obesity.119 A decrease in triacylglycerol content in the chylomicron lipoprotein fraction following acute diacylglycerol-oil versus triacylglycerol-oil intake was also shown in humans;120 other reported acute effects of diacylglycerol consumption in humans include lowering parameters of appetite and increasing fat oxidation and ketone body formation.121

Studies in humans support the potential value of diacylglycerol for the management of excess body weight and related disorders. In one study, carried out in 38 healthy non-obese and slightly overweight men, supplementation for 16 weeks with dietary diacylglycerol (provided at breakfast in the form of bread, mayonnaise and shortbread as part of an otherwise self-selected diet) resulted in decreases of body mass index, waist circumference, and visceral and subcutaneous adipose tissue greater than with tria-cylglycerol supplementation.122 In a weight-loss study carried out in 131 obese men and women, it was found that consumption of diacylglycerol oil as part of a reduced-energy diet enhanced loss of body weight and fat in comparison with consumption of a triacylglycerol control oil.123 Moreover, dietary diacylglycerol has been shown to suppress postprandial increases in serum lipid levels and to produce a higher postprandial energy expenditure and lipid oxidation compared with dietary triacylglycerol in humans,124125 and evidence has been obtained that diacylglycerol may be useful in the management of obesity and lipid abnormalities in both type 2 diabetic subjects and non-diabetic subjects with insulin resistance.126127

Diacylglycerol has been approved by the Japanese Government as a food for specific health use to control postmeal blood lipids and body fat128 and has recently been introduced in the EU as a novel food. Diacylglycerols occur naturally in small concentrations in several edible oils, cottonseed being among the richest. A diacylglycerol-rich cooking oil has been produced that contains about 80% diacylglycerols,128 the oil can be incorporated into foods or consumed as a salad dressing.

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