Review

International Journal of Obesity (2007) 31, 731–742. doi:10.1038/sj.ijo.0803500; published online 28 November 2006

The entero-insular axis and adipose tissue-related factors in the prediction of weight gain in humans

M-F Hivert1, M-F Langlois1 and A C Carpentier1

1Division of Endocrinology, Department of Medicine, Faculté de Médecine et des Sciences de la Santé, Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Québec, Canada

Correspondence: Dr AC Carpentier, Division of Endocrinology, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4. E-mail: andre.carpentier@usherbrooke.ca

Received 19 December 2005; Revised 9 August 2006; Accepted 15 August 2006; Published online 28 November 2006.

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Abstract

Obesity has now reached epidemic proportions. Epidemiological studies in the past decades have shown that adults gain weight and adiposity from the early twenties until their sixties. In the paediatric population, growing numbers of children and adolescents put on unhealthy weight. Many environmental, socio-economical and biological determinants that predispose to weight gain have been identified thus far. The aim of the present review is to summarize the current knowledge on the role of the circulating levels of adipokines and other entero-insular hormones and biological markers of obesity to predict weight gain in humans. The review focuses on relationship between hormonal and biochemical markers (insulin, insulin-like growth factors, gastrointestinal hormones, leptin, adiponectin, resistin, inflammatory proteins and cytokines) and weight gain in prospective studies. The complex relationships displayed by these hormonal factors with future weight gain in humans are critically reviewed and integrative models are proposed. Overall, most of the studies reported to date made adjustments for baseline body mass index but failed to consider dietary intake and physical activity as confounding factors. Outstanding questions are raised and new directions for future prospective studies are proposed in order to improve our understanding of the role of biological determinants of energy balance and development of obesity in humans.

Keywords:

adipokines, entero-insular axis, inflammatory markers, insulin, weight gain

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Introduction

Obesity and weight gain have been linked to sedentary lifestyles as well as dietary and socio-economic factors. Genetic or biological factors have also been related to weight gain and obesity such as parental obesity, low birth weight, early adiposity rebound and early puberty.1, 2 The biology of the entero-insular axis and adipose tissue and their complex interactions with other organs has become an effervescent field of research. More than just a storage compartments, the adipose tissue is an important endocrine organ, producing and secreting many proteins involved in the regulation of energy balance and in the adaptation of the human body to chronic toxic challenges imposed by our lifestyle.3 The aim of this original review is to summarize the current knowledge on the predictive value of adipokines and other entero-insular markers of obesity on weight gain from prospective studies in humans. It is also aimed at highlighting the predictive role of these biological variables relative to lifestyle and behavioural factors well known to influence the development of weight gain and obesity, although a thorough discussion of the biology of all of these factors is beyond the scope of the present review. MEDLINE was the original source for our search of the literature. Key words used were 'WEIGHT GAIN' and either 'INSULIN', 'INSULIN-LIKE GROWTH FACTOR', 'LEPTIN', 'ADIPONECTIN', 'RESISTIN', 'BIOCHEMICAL MARKER', 'INFLAMMATION', 'GHRELIN', 'PYY', 'PP', 'GLP-1', 'OXYNTOMODULIN', 'CHOLECYSTOKININ' or 'ENERGY HOMEOSTASIS'. We have included all prospective observational studies in humans that reported the relationship between weight gain and any of these hormonal or metabolic parameters between 1966 and November 2005. In addition, we have reviewed the bibliography of all manuscripts found during our MEDLINE search to complete our review.

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The entero-insular axis

Insulin

Elevated body mass index (BMI) is associated with higher fasting insulin and a lower degree of insulin sensitivity is found even in the non-obese range.4 Weight gain is also a potent predictor of the development of insulin resistance, irrespective of baseline BMI, both in adults5 and in children.6 The anabolic effect of insulin on peripheral tissues has been well studied over the past decades. Recent studies have supported a central anorexigenic effect of insulin.7 However, the precise physiological role of insulin with regard to feeding behaviour and control of energy balance in humans is still not fully elucidated.

Insulin level and insulin sensitivity in adult populations (summarized in Table 1)
 

The majority of prospective studies that included non-obese adults failed to show an association between insulin level at baseline and future weight gain. In the Ely Study,8, 9 fasting insulin levels were not associated with weight gain over more than 4 years of follow-up. The study by Zavaroni et al.10 included 647 middle-aged men and women with a mean BMI of 25.8 kg/m2 at baseline who had a baseline glucose tolerance test with a follow-up of 14 years. The 2-h post-75 g oral glucose insulin levels at baseline were not associated with future weight gain. Lakka et al.11 did not find an association between baseline fasting insulin and weight gain over 4 years in a middle-aged normo-insulinemic cohort of Finnish men. Masuo et al.,12 in a follow-up study of non-obese (mean BMI 21.2 kg/m2) Japanese men for 5 years, concluded that those individuals who gained weight (increase of >10% of initial BMI) did not differ in their baseline fasting insulin levels from those who did not.


On the other hand, other large cohort studies have shown that insulin resistance, which is usually associated with high plasma insulin levels, could be protective against weight gain. However, the results of these studies were strongly influenced by the level of obesity of the population under consideration. Folsom et al.13 compared the results of two major cohort studies in the United States: the Coronary Artery Risk Development in Young Adults (CARDIA) and the ARIC studies. In the CARDIA Study, no relationship was found between fasting insulin and future weight gain after adjustment for BMI in a cohort of young African-American and Caucasian adults with normal weight. In comparison, the ARIC Study found a weak negative relationship between fasting insulin and subsequent weight gain (after adjustment for baseline weight) in a cohort of middle-aged African-American and Caucasian adults with a mean BMI of over 27 kg/m2. In the San Luis Valley Diabetes Study,14 a negative relationship between fasting insulin and subsequent weight gain was observed in Hispanic and non-Hispanic white subjects (mean BMI over 25 kg/m2), although this relationship was much stronger in individuals with a higher BMI. In the San Antonio Hearth Study,15 a higher baseline insulin level was associated with less weight gain but only in the most obese tertile of this cohort. In obese adult Pima Indians (mean baseline BMI of 34 kg/m2), insulin resistance was associated with a reduced rate in weight gain.16, 17 Hodge et al.18 also found that insulin resistance was negatively correlated with weight gain in Asian Indian and Creole populations of Mauritius, although the relationship was not statistically significant after adjustment for age and BMI. In the latter study, in contrast to the findings in the two other ethnic groups, insulin resistance was positively associated with weight gain in Chinese men (even after adjustment for BMI). Similar findings were also noted in second generation of Japanese-American men who immigrated in America. In a 5-year follow-up cohort of middle-aged Japanese-American men (BMI 25.5 kg/m2),19 baseline fasting insulin and C-peptide were not predictors of change in BMI but were positively correlated with an increase in visceral fat measured by computed tomography scan. Thus, it is possible that the Asian genetic background modifies the relationship between insulin resistance, BMI and weight gain observed in other populations.

Increased insulin secretion occurs as an adaptive response to decreased insulin sensitivity. Some cohort studies have examined the association between insulin secretion and weight gain. In Pima Indians,17 insulin secretion was negatively associated with the rate of weight gain, whether assessed by the insulin response during a meal tolerance test, an oral glucose tolerance test or the acute insulin secretory response to intravenous glucose. Boyko et al.19 showed that reduced insulin secretion precedes visceral fat accumulation in non-diabetic Japanese-American men. Similarly, Gould et al.9 demonstrated that a low insulin response 30 min post-75 g oral glucose challenge was predictive of higher weight gain in Caucasian women but found no such association in men. In contrast to these findings, Sigal et al.20 studied weight gain in offspring of two parents with diabetes. The authors failed to find a correlation between fasting insulin and weight gain (similar to the results from many other cohorts, as mentioned above), but did show that high acute insulin response during an intravenous glucose challenge was a predictor of higher weight gain, especially in insulin-sensitive subjects. This is actually not in complete discordance with earlier findings. Indeed, the predictive effect of high acute insulin response on weight gain was diminished in insulin-resistant subjects. Thus, it is possible that at the onset of the weight gain process, insulin may act as an anabolic hormone and conceivably induce fat accumulation. As adiposity increases, insulin resistance develops and may eventually protect the individual against further weight gain.

Insulin level and insulin sensitivity in pediatric populations (summarized in Table 2)
 

Prospective studies were also performed in younger populations to evaluate the relationship between insulin levels and change in weight. Unfortunately, a clear picture has yet to emerge from currently available studies. Some studies have found a positive association between hyperinsulinemia and future weight gain. For example, Johnson et al.,21 in a longitudinal follow-up study of a biracial cohort, found that a higher fasting insulin level or a higher acute insulin response to an intravenous glucose tolerance test was predictive of higher gain in fat mass (measured by Dual-energy X-ray absorptiometry (DEXA)). Odeleye et al.22 monitored overweight (mean weight: 119% of ideal body weight) Pima Indian children aged between 5 and 9 years old with normal glucose tolerance. Elevated fasting insulin levels were positively associated with weight gain over a 9.3-year follow-up period. Savoye et al.23 found similar result in a biracial cohort of children followed for 2.5 years. Fasting insulin levels were positively correlated with changes in BMI in obese children (both boys and girls) and in teenage boys (but not in teenage girls). In contrast to these studies, Salbe et al.24 reported that low baseline insulin levels predisposed subjects to more weight gain after 5 years of follow-up in 5-year-old Pima Indian children (116–118% of ideal body weight). Similarly, Maffeis et al.25 followed obese or overweight (mean relative BMI over 150%) Caucasian children over 14 years of age and found that a high insulin resistance index, estimated by the homeostasis model assessment model, was associated with a reduced likelihood of obesity in adulthood. However, this relationship was found only in girls with confidence intervals (CIs) of the odd ratio (OR) very close to 1.0. In fact, other cohort studies have not shown any association between insulinemia and subsequent weight gain. The Bogalusa Heart Study26 followed 427 children, 674 adolescents and 396 young adults for 3 years. An association between BMI and weight gain with follow-up insulinemia was found, but no significant relationship was found between baseline insulin levels and follow-up BMI after adjustment for baseline BMI. Byrnes et al.27 surveyed a small cohort of 37 boys and girls and did not find an association between fasting insulin or the insulin:glucose ratio and weight gain over 12 months. Thus, the relationship between insulin levels and resistance and weight gain in children remains controversial.


In summary, although a negative correlation between plasma insulin level or insulin resistance and future weight gain has been observed more consistently in overweight adults, this relationship was not consistently shown in lean adults and in pediatric populations. One possible explanation for these observations is a threshold effect: at the onset of the process leading to weight gain, overweight induces more insulin resistance with an increase in insulin secretion contributing to future adipose tissue accumulation. When this accumulation reaches a certain level (threshold), insulin resistance becomes high enough to oppose further fat accumulation in adipocytes and/or to send negative feedback as an anorexigenic signal at the level of the hypothalamus to limit further weight gain. This biphasic longitudinal relationship between insulin levels and weight gain has been demonstrated by Lazarus et al.28 in their study of the temporal trends between plasma insulin levels and changes in weight in 376 Caucasian men by measuring body weight and fasting insulin at various points in time. Higher initial weight gain (Deltaweight1 over 3.7 years) was correlated with higher subsequent fasting insulin (measured at the end of the period covering Deltaweight1). Thereafter, fasting insulin level was negatively correlated with changes in weight over the subsequent follow-up period (Deltaweight2 over 3.3 years).

IGFs

Insulin-like growth factor (IGF)-1 is produced by the liver in response to growth hormone and is essential for normal linear growth during childhood and adolescence. IGF-II, on the other hand, plays a role in the proliferation and differentiation of foetal cells but its role in post-natal development remains obscure.29 IFG-I and IGF-II levels in cord blood have been shown to correlate with birth weight. IGF-I levels measured at age 5 were higher in children who had a low birth weight and a rapid early growth rate (catch-up growth), whereas IGF-II levels were directly related to levels at birth.30 Low IFG-II levels have been associated with higher BMI and low physical activity levels in cross-sectional studies in adults.31

The Ely Study8 examined the relationship between many biological factors (IGF-I, IGF-II, fasting insulin, cholesterol, triglyceride (TG), non-esterified fatty acid, leptin and glucose level 2 h after a 75 g oral glucose tolerance test) measured at baseline and future weight gain in 463 non-obese middle-aged men and women (mean BMI 24.2 kg/m2). The 246 individuals who lost weight (lost >2.5 kg) or kept their weight stable (plusminus2.5 kg) were compared with the 217 individuals who gained weight (>2.5 kg) over the 4.4 years of follow-up. The only factor statistically different between the two groups at baseline was IGF-II. The level of IGF-II was inversely associated with the risk of weight gain and the development of obesity, an association that remained significant in multivariate analyses.

GI hormones

In recent years, important advances have been made in our understanding of the mechanisms of appetite regulation by gastrointestinal (GI) hormones. These hormones include ghrelin, the pancreatic polypeptide (PP)-fold peptides, peptide YY (PYY), proglucagon products, oxyntomodulin (OXM), glucagon-like peptide (GLP-1, GLP-2) and cholecystokinin (CCK).7

Ghrelin is mainly produced by the oxyntic cells of the gastric mucosa and is regarded as a short-term orexigenic hormone. In humans on a fixed feeding schedule, its plasma level is elevated during fasting, rises before meals and decreases after ingestion of food.32 Ghrelin stimulates food intake most likely by increasing the levels of neuropeptide Y and agouti-related protein in the arcuate nucleus of the hypothalamus. The injection of ghrelin acutely increases food intake and repetitive administration increases body weight because of a chronic increase in food intake.33 Circulating ghrelin is usually lower in obese individuals and has been shown to increase following diet-induced weight loss.32 Obese subjects do not demonstrate the rapid post-prandial drop in ghrelin levels observed in normal-weight individuals.7 Ghrelin levels are high in anorexia nervosa and decrease with restoration of normal weight.33 Thus far, only one prospective study investigating the predictive value of ghrelin on weight gain in humans has been reported.34 In this study, 40 10-year old Pima Indian children (27girls and 13 boys) were followed over a period of 1.7 years. No significant association was found between baseline ghrelin levels and changes in weight, height or adiposity (measured by DEXA).

PYY, PP, GLP-1, OXM and CCK are gut-derived hormones that all have demonstrated anorexic effects during short-term experiments.7, 35, 36, 37 However, a detailed discussion on the biological regulation of these hormones is beyond the scope of the present review. Although experimental studies have certainly enhanced our knowledge of the regulation and complex interactions between GI hormones and short-term energy intake and expenditure, much work is still needed to fully understand the complex phenomenon of appetite control and its impact on weight gain in free-living human populations. To date, with the exception of ghrelin, prospective studies have yet to explore the potential link between these important GI hormones and weight gain in human populations.

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Adipokines

Leptin

Leptin is an adipose tissue hormone produced proportionally to subcutaneous adipose tissue mass. Food restriction over a period of days also lowers leptin levels and, conversely, leptinemia can be raised back to normal by re-feeding.7 Overfeeding over a period of 3 days was also shown to increase leptin levels.38 Therefore, leptinemia reflects both energy stores (adipose tissue) and recent food intake.

Leptin levels in adult populations (summarized in Table 3)
 

Although circulating leptin level is currently regarded as a marker of adiposity, controversy remains regarding its potential role in weight change in humans. Most cohort studies in non-obese adults did not find an association between baseline leptin levels and future weight gain. This absence of correlation seems to be consistent in many ethnic backgrounds. In the Mexico City Diabetes Study,39 180 non-diabetic men and women were followed over a 3-year period with no relationship found between leptin levels and weight gain. In Mauritius, Hodge et al.40 has shown no association between leptinemia and weight gain in 2888 individuals over a 5-year follow-up period. Similarly, Masuo et al.12 found no relationship between leptin and weight change over 5 years in a cohort of middle-aged Japanese men (BMI<25 kg/m2). The Ely Study,8 described earlier, did not show any association between baseline leptin and subsequent weight gain. In the United States, Folsom et al.41 measured baseline leptin levels in a subgroup (n=492) of their young adult cohort (Caucasian and African Americans). They observed an average weight gain of 7.8 kg over 8 years, but no association could be demonstrated between baseline leptinemia and the degree of weight gain. However, two other studies found opposite results. In a cohort of middle-aged normal weight Swedish women,42 a high leptin level at baseline was predictive of subsequent weight gain but only in women less than 50 years old. In this study, the authors had subdivided the normal weight from the overweight women at baseline, but did not adjust the correlation for BMI levels within the strata. Van Rossum et al.43 found higher baseline leptin levels in individuals who gained an average of 12.6 kg over 6.8 years compared to individuals whose weight remained stable from a cohort of 259 normal weight young Dutch. However, in this study, leptin levels were measured at random, not necessarily in the fasting state. Moreover, the individuals who gained weight tended to be heavier than the control group, and when adjusted for BMI, the inferior limit of the CI of the OR was very close to one (OR 1.28; CI=1.01–1.61), suggesting that the relationship between high plasma leptin levels and future weight gain may have been driven to a large extent by the initial difference in BMI.


Studies performed in overweight and obese adult populations found more convincing evidences of a relation between leptin levels and future weight gain. The Health Professionals Follow-up Study44 demonstrated that increased leptin levels are associated with more weight gain, but only in overweight men. Chessler et al.45 showed that increased plasma leptin levels are associated with fat accumulation in second- and third-generation Japanese-American men and women. This latter cohort included diabetic and non-diabetic individuals and should be considered as overweight (average BMI 24.4 kg/m2) because BMI values of 22.9 and 25.0 kg/m2 are now considered as cutoff thresholds for overweight and obesity, respectively, in Asian populations.46 In contrast, other investigators have found that high plasma leptin levels predict less weight gain in obese subjects. Ravussin et al.47 followed obese (BMI 35.3 kg/m2) Pima Indians over a period of 3 years. The 19 subjects who gained weight (average weight gain: 23 kg over 3 years) had lower leptin levels at baseline than the 17 subjects with stable weight. Similarly, Lindroos et al.,48 in a follow-up study of 49 women with BMI>40 kg/m2 over a 4-year period, noted that high baseline leptin levels predicted less weight gain, but the association was statistically significant only in woman with no obese parent and was closely related to dietary changes. It should be pointed out that the latter two studies included individuals with much higher BMI than the previous mentioned studies. Thus, the available data from prospective studies suggest that, in overweight adults, leptin levels are positively associated with weight gain whereas in obese adults, high leptinemia is associated with less weight gain.

Leptin level in pediatric populations (summarized in Table 4)
 

During childhood and adolescence, circulating leptin levels change and probably play a permissive role in the initiation of puberty.49 In prepubertal children, leptin levels are similar in boys and girls. During the transition between the prepubertal to the post-pubertal period, leptin levels rise in girls in relation to the increase in adiposity whereas leptin levels decrease during the same period in boys.49 In 176 Pima Indian children24 followed from age 5 to 10, a higher baseline leptin level was a predictor of greater weight gain. Savoye et al.23 showed similar findings with a cohort of 68 obese children (Caucasian and African Americans) over a 2.5-year follow-up period. In their study, a higher leptin level at baseline was predictive of greater weight gain, but in girls only. Similarly, Johnson et al.50 found that a high leptin level at baseline was a predictor of increased fat mass in a cohort composed of 85 Caucasian and African-American children. In contrast, Byrnes et al.27 followed 37 Caucasian children (boys and girls with a wide range of BMI) over 12 months and found that a low leptin level was a predictor of higher increase in BMI. Similarly, Ahmed et al.51 noted that a low leptin level in prepubertal girls (8 years old) was followed by a greater gain in percent body fat (but not in absolute fat mass). Although the results from these pediatric cohorts are divergent, the bulk of evidence suggests that high plasma leptin levels may be a predictor of future weight gain. Whether this association is related to confounding variables such as BMI, gender and time of onset of puberty will require more detailed studies in this population.


In summary, the contribution of leptin to weight change throughout development and adulthood in humans is still not completely understood. As leptin levels are closely related to BMI and fat mass, could the relationship between leptinemia and future weight gain be different depending on the degree of adipose tissue excess, similarly to the relationship observed between insulin levels and weight gain? In the overweight stage, higher leptin may predict more weight gain (as a marker of active adipose tissue growth) and when obesity is well established, high leptin levels (as a marker of very high adiposity and high degree of insulin resistance) may predict less future weight gain. In addition to the major contribution of body composition, plasma leptin levels have been shown to change within days after either a reduction52 or increase in energy intake.38 Some investigators have also shown a variation in leptin levels with exercise.53 The acute influence of energy intake and expenditure on plasma leptin levels underscores the importance of taking into account acute dietary intake and physical activity when assessing the potential role of leptin on chronic energy balance and future weight change. Forthcoming studies assessing the role of this hormone on weight change will ultimately need to take these factors as well as BMI into consideration.

Adiponectin

Adiponectin is an adipokine that is produced by mature adipocytes and plasma levels are inversely related to visceral fat accumulation.54 Circulating levels of adiponectin increase after food restriction and following weight loss.7 Plasma adiponectin levels are lower in individuals with insulin resistance, type 2 diabetes and visceral obesity in cross-sectional studies, even in young adult populations.55 Adiponectin improves insulin sensitivity, inhibits vascular inflammation and may have direct antiatherosclerotic effects.56 For the same degree of obesity, a lower adiponectin level is a predictor of a higher degree of insulin resistance.57 Adiponectin serum concentrations have been shown to increase after weight loss.7 The only prospective study exploring a possible relationship between plasma adiponectin levels and subsequent weight gain was performed in 219 obese non-diabetic Pima Indians with no association reported between weight changes and baseline serum adiponectin.58

Resistin

Resistin is produced in the stromovascular fraction of adipose tissues and in peripheral blood monocytes, suggesting a possible role in the inflammatory state associated with obesity.59 Although a very exciting role for resistin in the modulation of insulin sensitivity was initially observed in rodent models,60 evidence in humans is still conflicting.61 Resistin is positively related to the percentage of body fat and BMI.62 Patients with type 2 diabetes treated with thiazolidinedione showed a significant reduction in plasma resistin concentrations.63 In this latter study, the decrease in plasma resistin was correlated with a decrease in hepatic fat content and improvement in hepatic insulin sensitivity. In one study, 113 non-diabetic Pima Indians were followed over 4.5 years with the demonstration of a positive correlation between high resistin levels and an increase in percent body fat.64

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Inflammatory proteins and cytokines

Resident macrophages of the adipose tissue and white adipose tissue itself also produce C3, adipsin and factor B that are required for the production of acylation-stimulating protein (ASP).65 C3 and Factor B are positively correlated with body weight and visceral fat, and decrease after weight loss66, 67 ASP secretion by the adipose tissue is increased after meals and stimulates TG synthesis and decreases non-esterified FA release in adipocytes.65 Levels of plasma ASP have been positively correlated with obesity, percent body fat and with insulin resistance.65 However, there are currently no reported prospective studies that have assessed the potential role of ASP in weight change and in the development of insulin resistance in humans.

Tumor necrosis factor (TNF-alpha) is involved in the pathophysiology of obesity and insulin resistance. Large adipocytes produce more TNF-alpha which in turn inhibits adipocyte differentiation, promotes lipolysis and impairs insulin signalling.68 Interleukin-6 (IL-6) is produced by cells of the innate immune system as well as by adipose tissue.69 IL-6 plasma levels are increased in obesity, glucose intolerance and type 2 diabetes70 and IL-6 alters insulin sensitivity, regulates hepatic production of fibrinogen and C-reactive protein, is procoagulant and stimulates adhesion of circulating leucocytes to the vascular endothelium.69 In Spanish overweight men and women, elevated IL-6 was correlated with high circulating serum levels of saturated and omega-6 polyunsaturated fatty acids.71 On the other hand, IL-6 levels in the central nervous system negatively correlate with obesity and fat mass.72 This suggests that IL-6 may not directly cause human obesity, but enhanced peripheral production of IL-6 may occur as a result of the development of obesity and/or from increased dietary fat content. Whether TNF-alpha and IL-6 are primarily involved in the pathogenesis of human obesity and insulin resistance or perhaps secondary to an unhealthy lifestyle is still largely unknown.61 Future prospective studies in humans should help clarify this issue.

Proteins involved in the coagulation cascade are often markers of vascular reactivity and inflammation. Obesity has been linked to higher levels of fibrinogen and von Willebrand factor in cross-sectional studies.73 Two studies have investigated whether these markers of chronic subclinical inflammation may predict weight gain in humans. In the ARIC Study,74 13 017 overweight men and women aged 45–64 years old were followed prospectively for approximately 3 years. An increase in weight gain was observed in individuals who were in the highest quartile of fibrinogen, von Willebrand factor, factor VIII and white blood cell levels, even when adjusted for potential covariates. Of these factors, fibrinogen levels appeared to be the most potent predictor of weight gain, an effect even stronger when analysing obese individuals separately. In Sweden, similar results have been obtained with other inflammatory proteins (fibrinogen, orosomucoid, alpha1-antitrypsin, haptoglobin and ceruloplasmin).75 A cohort of 2821 non-diabetic men with a mean BMI of 24.7 kg/m2 at baseline (aged between 38 and 50 years old) were followed for more than 6 years. The chance of substantial weight gain (greater than or equal to3.8 kg) increased with the number of inflammatory proteins in the highest quartile (OR 1.51 for greater than or equal to3 proteins in the top quartile). This was true independently of baseline BMI and other confounders, although the effect was stronger in those individuals with a BMI>28 kg/m2 and in non-smokers. High fibrinogen, ceruloplasmin and orosomucoid levels were also individually associated with greater weight gain after adjustment for confounders.

In summary, manifestations of subclinical chronic inflammation appear early during the process of weight gain and likely play an active role in the metabolic and cardiovascular complications associated with obesity. One intriguing possibility is that high dietary fat intake could enhance and/or activate this chronic inflammatory process while contributing to the development of obesity by inducing chronic energy excess. Elevated plasma lipids could lead to the enhanced inflammatory response associated with obesity, insulin resistance and T2DM.76 Transient proinflammatory activation of blood monocytes have been demonstrated in the first 3 h following a mixed meal in healthy subjects.77 The interaction between diet composition and activation of the inflammatory responses constitutes a major area of research warranting future investigation in humans.

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Conclusions

The demonstration of a role of insulin and leptin in predicting weight gain has been inconsistent in the many prospective studies that have been conducted to this day. These hormones appear to display a complex relationship with the risk of weight gain, seemingly not affecting normal-weight population but positively associated with higher weight gain in overweight individuals, and inversely related to weight gain in more obese populations. Complex interactions between the potential effects of these hormones on weight gain and the varying degree of insulin resistance throughout the process leading to the development of obesity cannot be ruled out. Furthermore, the potentially confounding effect of acute dietary and lifestyle factors on these hormones and their association with weight change has been overlooked in most studies to date.

Thus far, adiponectin and ghrelin do not appear to be good predictors of weight gain, although we still have relatively few prospective data on the potential predictive role of these hormones. IGF-II levels have been shown to predict future weight gain in a well-conducted study that included a fair number of participants. This finding clearly needs confirmation in other populations. The role of resistin in weight gain in humans is still obscure, and the positive link with fat gain observed in Pima Indians also needs to be confirmed in other populations.

The relationship between high circulating levels of several proteins involved in chronic subclinical inflammation and coagulation and future weight gain appears to be strong in prospective studies reported thus far. Whether this stems from a causal relationship or whether it is a manifestation of the unhealthy lifestyle involved in the triggering of chronic subclinical inflammation, endothelial dysfunction, and chronic, slow, unrelapsing gain in adiposity observed throughout infancy and adulthood in our developed societies will ultimately require more investigation.

This review underlines the relative lack of prospective studies investigating biological markers and potential mechanisms involved in the development of overweight and obesity in humans. In particular, there is yet to be a study that has addressed the relative role of biological markers as opposed to lifestyle as well as the interaction between these factors in the development of obesity. A greater integration of knowledge is needed in order to not only further our understanding of the most important mechanisms involved in the development of obesity in our societies, but also to efficiently tackle this menacing epidemic.

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Acknowledgements

MFH is a post-doctoral fellow supported by the Merck-Frosst-Scherring-Université de Sherbrooke Fellowship Award. ACC is the recipient of a New Investigator Scholarship Award from the Canadian Institutes of Health Research (MSH 46799). MFL is the recipient of a Junior-2 clinician-researcher scholarship from the Fonds de la recherche en santé du Québec.

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