The biology of obesity

The cornerstone of any dietary treatment of obesity is reduction of energy intake, and sustainment of a lower energy intake to prevent weight regain. Camilla Verdich, PhD, and colleagues discuss the role of fat, carbohydrates and protein on body weight

By the year 2000, being overweight or obese was more common than being normal weight among the adult population in many European countries and the US.1 Although fat intake is one of the potential obesity-promoting factors that has gained more attention in obesity research, the role of fat intake in the development of obesity is still controversial, and the findings are not consistent.2 In animal models, changing from a low-fat diet to a high-fat diet leads to an increase in body fat and an increase in the inter-individual and inter-strain variation in body fat, suggesting a genetic susceptibility to becoming obese on a high-fat diet.3^,4

Cross-sectional studies have indicated positive associations between dietary fat energy per cent and body weight, but such studies cannot distinguish between the possible effects of obesity on fat intake, vice versa, or common effects on both obesity and fat intake of an underlying third factor.

There are some paradoxical observations regarding the relationship between reported fat intake and obesity that raise the suspicion that there is no simple relation between the two. In the US and in many European countries, fat intake has decreased during the last decade, whereas the prevalence of obesity has increased. This may be interpreted as an indication that reducing dietary fat may not lead to a concomitant reduction in obesity. However, increased under-reporting of fat intake may bias these observations,5 and subgroups of the population may have increased their fat intake and become obese, whereas others may have reduced their fat intake.

In line with the findings from animal models, a high habitual fat energy percentage has been shown to be associated with a high mean body mass index, as compared to low-fat consumers.6 Another common feature between animal and human studies is that between-subject variation is higher in high-fat consumers, and that some individuals appear to be protected from developing obesity even when consuming a high-fat diet.6

Results from prospective observational studies do not support the hypothesis that high fat intake leads to later obesity. However, these studies are inconsistent and may be confounded by people modifying food intake in order to prevent changes in body weight or that for other reasons the baseline food recording does not reflect food habits during the follow-up period.2

Intervention studies generally support the hypothesis about a relationship between fat intake, energy intake and eventual weight change. Ad libitum intake of a low-fat diet has been shown to induce a mean weight loss of 1-4kg over a period of one to 12 months, and has further shown a dose-response relationship between the reduction in fat intake and weight loss.7

Fat content and energy density of the diet are highly correlated, and only a few studies have targeted the effect of energy density and fat content separately. These studies have indicated that energy density, rather than fat content per se, may favour an increase in energy intake. However, it might be hypothesised that in subjects with a genetic predisposition to low fat oxidation and high fat accumulation in adipose tissue, fat intake per se could be expected to promote obesity. Further, genetic factors may influence the satiety effect of fat and the preference for fat, and may cause some people markedly to increase their food intake in response to a high-fat diet. Taken as a whole, animal studies, epidemiological observational studies and intervention studies offer substantial support to the hypothesis that high-fat energy percentage or high energy density may play a role in the development of obesity.

Carbs and protein
Increases in dietary carbohydrate and protein energy percentage will cause a reduction in dietary fat energy percentage, and vice versa. Epidemiological studies have suggested a positive association between fat-sugar ratio in the diet and BMI.8

With respect to the type of carbohydrates, intervention studies have indicated no differences in weight loss during intake of a low-fat diet rich in either simple or complex carbohydrates.9 However, there is evidence that high intake of simple carbohydrates in liquid form (soft drinks) may predispose to weight gain.10

Animal studies have indicated inverse relationships between dietary protein content and energy intake with between-strain differences in response, which suggest a nutrient-gene interaction.3 Intervention studies have suggested that a low-fat, high-protein diet may lead to a larger weight reduction compared with a low-fat, high-carbohydrate diet.11 Recent intervention studies suggest that low-carbohydrate, high-protein diets may be superior to the low-fat, high-carbohydrate diet in terms of weight reduction.12^,13 However, large-scale intervention studies are required to determine long-term safety and efficacy of these dietary strategies for both prevention and treatment.

Dietary strategies
Several strategies exist for inducing weight loss in overweight and obese subjects. However, in most cases long-term success is limited because the majority of subjects regain all lost weight within three to five years. Obesity is a chronic condition, and it therefore seems evident that some form of life-long intervention may be needed in order to maintain weight loss in obese subjects. On the other hand, the long-term benefit of this strategy is not as obvious as it might look.

Thus, there is an ongoing debate regarding the evidence suggesting that weight reduction, although having beneficial effects on risk factors for cardiovascular disease and type 2 diabetes, may be associated with increased long-term mortality.14^,15 Evidently, improved primary prevention of weight gain in obesity-prone subjects, combined with improved strategies for management of obesity, are the main tasks for the future.

Future large-scale, multi-disciplinary projects should aim at optimising the use of new research methods in combination with existing research methods. Metabolomics and proteomics, combined with gene expression profiling and genotype screening, may provide new important insights into the system biology of obesity. This may further allow the identification of candidate pathways involved in the development of obesity, and thereby the identification of candidate drug targets for treatment and prevention of obesity, as well as biomarkers indicating the efficiency of the pathways on the individual subject level.

It may be speculated that although a large number of genes and a complex interplay of environmental and genetic factors determines body fat accumulation, the number of pathways mediating the effect of these factors on body fat accumulation may be limited. Identifying the pathways could serve as a platform for a new classification, diagnostic and treatment of the common complex forms of obesity. Further, identifying biomarkers reflecting susceptibility to particular nutrients in pre-obese subjects would be a crucial step in the primary prevention of obesity.

Foods to improve lipogenesis¹⁶
When dealing with the regulation of a specific metabolic pathway in a given direction by functional foods, it is obviously necessary that the specific nutrients chosen have no adverse consequences that will alter the global health status. The other necessity is that the functional food can be used at a reasonable dose compatible with an otherwise normal nutrition.

Is it advantageous to modulate the lipogenic rate — that is, the rate of fat formation in the body? Hyperlipidaemia with high concentrations of VLDL-triglycerides is associated with insulin resistance, obesity and cardiovascular diseases.

Plasma triglyceride concentration is dependent upon the rates of hepatic VLDL production and of clearance from the plasma. Hepatic lipogenesis from carbohydrates can contribute significantly to the rate of triglyceride production by the liver in conditions such as obesity or when ingesting simple-sugar enriched diets. It is thus reasonable to try to decrease de novo fatty acid synthesis. In addition, this could favour hepatic fatty acid oxidation by reducing malonyl-CoA concentration, thus alleviating the inhibition of CPT I, and ultimately improve hepatic insulin sensitivity.17

PUFAs: At present, two directions can be explored. The first one involves the use of polyunsaturated fatty acids (PUFAs) of the n-3 and n-6 families. Small amounts of PUFAs in the diet are able to reduce very efficiently the hepatic rate of lipogenesis at least in rodents. 18 In addition, this effect is specific of hepatic lipogenesis. Moreover, PUFAs have been described as potentially beneficial for atherosclerosis. 19 Thus, the use of PUFAs is an interesting clue as a beneficial modulator of hepatic lipogenesis.

Prebiotic fibres: The second possibility involves the use of nondigestible oligosaccharides belonging to the fructan class such as inulin or one of its fraction oligofructose. They are usually obtained from chicory roots or Jerusalem artichokes. These oligosaccharides are not digested in the upper intestine because the anomeric carbon 2 in their fructose momomer is in a beta configuration precluding hydrolysis by human digestive enzymes, which are specific for alpha-glycosidic bonds.20

Inulin and oligofructose are thus fermented in the caeco-colon, yielding short-chain fatty acids such as acetate, butyrate and propionate. It has been repeatedly shown in rodent models that inulin and oligofructose given in a 10 per cent range in the diet are able to modulate triglyceride metabolism at the hepatic level.21

When fed with oligofructose-enriched diets, a lower triglyceridaemia in nonobese animals and a decreased hepatic steatosis in Zucker fa/fa obese rats have been observed.21 A lower rate of lipogenesis due to a reduction in the expression and activity of lipogenic enzymes seems to be a key explanation for the effects of these oligosaccharides.21

In humans, conflicting results have been reported concerning the effect of inulin and oligofructose in lipid metabolism.20 Some studies have reported a beneficial effect on serum triglycerides where others have not. It must be underlined that the doses used in humans are much lower than in rats due to the unpleasant gastrointestinal effects when consuming doses in excess of 30g/day.

In addition, if lipogenesis is one of the key targets of their effects, then the diet fed during the study is of importance.20 It can be predicted that the antilipogenic effects of fructans would increase with the sugar content of the diet.

A recent study has addressed the question of the effects of fructans on hepatic lipogenesis in humans.22 Inulin (10g/day) was added to a moderately high carbohydrates diet (55 per cent of total energy). Plasma triglycerides and hepatic lipogenesis were indeed lower in the group consuming the inulin-enriched diet.

Finally, it can be pointed out that fructans that are already widely used in the food industry (texture modifier, sweetener) have no obvious adverse effects and are even usually considered as having health-promoting properties. 20

Future trends
One of the most important future issues in the field of lipogenesis is the confirmation of its regulatory role in food intake and in the fatty acid oxidation and hence resistance to obesity. Decreased lipogenesis in liver and muscle should favour fatty acid oxidation. This in turn would favour weight loss by a yet unknown mechanism but which could be linked to an uncoupling effect of fatty acids on the mitochondrial respiratory chain. However, an inhibition of lipogenesis in specific hypothalamic nuclei would mimic starvation and thus should increase food intake and favour weight gain. Activation of the lipogenic pathway would thus have an opposite effect on weight.

Part of the problem would then be to find a way of reaching only one of the two regulatory systems. PUFAs might be one possibility. Indeed, they reduce hepatic lipogenesis in animal models and do not enter readily into the brain. However, the reality of this effect needs to be studied convincingly in humans.

Concerning fructans, a number of problems has to be solved. The links between fructan fermentation and effects on gene expression are not entirely clear and this kind of experiment must be repeated and further analysed in different models. The effects of fructans on human lipid metabolism must be addressed in a more systematic way.

The effect of fructans on hepatic steatosis in obese rats is particularly interesting since in humans, Non-Alcoholic Steato-Hepatitis is diagnosed in a large percentage of obese people and has been associated with the metabolic syndrome.23 Whether such an effect of nondigestible oligosaccharides can be observed on the steatosis of patients is also an interesting issue that needs to be documented.

Camilla Verdich, PhD, and TIA Sorensen, PhD, are at Copenhagen University Hospital, Denmark. Karine Clement, Fabienne Foufelle, PhD, and P Ferre are with INSERM, France, the French National Institute for Health and Medical Research. Excerpted from Functional Foods, Ageing and Degenerative Disease, C Remacle and B Reusens, editors. ISBN 0-8493-2538-2. Published by Woodhead Publishing Ltd, England. www.woodheadpublishing.com

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