Claudio Maffeis

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Influence of diet, physical activity and parents' obesity on children's adiposity: a four-year longitudinal study.

OBJECTIVE: To assess the relationships between diet, body composition, physical activity, parents’ obesity and adiposity in children at the age of 8 y and four years later.STUDY DESIGN: Prospective observational study of anthropometric measures initiated in 1992, follow-up examination in 1996.METHODS: 112 prepubertal (age: 8.6±1.0 y) children were studied. Energy and nutrient intakes were assessed by diet history, body composition by anthropometry and physical activity, by a questionnaire. Obesity was defined as relative body mass index (BMI) (rel BMI)>120%, where rel BMI=(BMI/BMI at 50th centile for age and gender)×100.RESULTS: Prevalence of obesity was not statistically different at baseline (22.3%) than four years later (19.8%): rel BMI at the age of 8 y was positively self-related with rel BMI at the age of 12 y (r=0.73, P<0.001). After four years, eight (32%) obese children became non obese and five (6%) non obese children became obese. Multiple regression analysis (stepwise procedure) revealed that, in the final equation, the mother’s BMI and TV viewing (independent variables) accounted for 17% of the children’s rel BMI variance at the age of 8 y (R=0.42, P<0.001) while the parents’ BMIs accounted for 13.5% of the children’s rel BMI variance at the age of 12 y (r=0.37, P<0.001). Other variables such as total energy intake, nutrient intake percentage and amount of physical activity, were all rejected. An autoregressive unbalanced measures model regression analysis recognised the mother’s and father’s BMIs as the only variables able to predict rel BMI in the children (mother’s BMI coeff. 2.53 (s.e.m. 0.26), P<0.0001; father’s BMI coeff. 2.07 (s.e.m. 0.23), P<0.0001). A multivariate logistic regression analysis was also performed. The children who participated in the follow-up, were divided into two groups based on the positive or negative change in the rel BMI between final and baseline measurements. Of all the variables considered, only rel BMI at baseline was selected in the final equation. Other variables such as age, gender, energy and nutrient intake, TV viewing and amount of physical activity, as well as the parents’ BMI, were all removed.CONCLUSIONS: The parents’ obesity was the main risk factor for obesity in this group of children. Sedentary behaviour (TV viewing) was independently associated with overweight at the age of 8 y. Physical activity and energy and nutrient intakes did not significantly affect the change in rel BMI over the four-year period when the parents’ obesity was taken into account.

Waist-to-Height Ratio, a Useful Index to Identify High Metabolic Risk in Overweight Children

OBJECTIVE To determine whether using a combination of body mass index (BMI) and waist circumference (WC) or waist-to-height ratio (W/Hr) is clinically helpful in identifying children with high metabolic and cardiovascular risks. STUDY DESIGN Caucasian children (M/F: 740/739; n = 1479; ages 5 to 15 years) were studied. Anthropometry, blood pressure, and venous fasting blood samples tested for triacylglycerol, HDL cholesterol, and glucose were measured. RESULTS Overweight children with a large waist (>90(th) percentile) or high W/Hr (>0.5) but not obese or normal-weight children had significantly greater chances of being at high metabolic and cardiovascular risk than normal-weight children (OR: 7; 95% CI: 3.63-13.48; P < .001, OR: 8.16; 95% CI: 3.87-17.23; P < .001, respectively) with a low waist measurement (</=90(th) percentile) or W/Hr (</=0.5). Interestingly, waist and W/Hr cutoffs (90(th) percentile and 0.5, respectively) were both able to identify children with the highest metabolic and cardiovascular risks among those who were overweight. However, contrary to waist circumference, W/Hr has the advantage of not requiring population specific reference tables as well as age and sex specific cutoffs. CONCLUSIONS Waist circumference and W/Hr are helpful in detecting, among overweight children, those with a higher likelihood of having metabolic and cardiovascular risks.

Aetiology of overweight and obesity in children and adolescents.

Abstract The epidemic diffusion of obesity in industrialised countries has promoted research on the aetiopathogenesis of this disorder. The purpose of this review is to focus mainly on the contribution that European research has made to this field. Available evidence suggests that obesity results from multiple interactions between genes and environment. Parents obesity is the most important risk factor for childhood obesity. Twin, adoption, and family studies indicated that inheritance is able to account for 25% to 40% of inter-individual difference in adiposity. Single gene defects leading to obesity have been discovered in animals and, in some cases, confirmed in humans as congenital leptin deficiency or congenital leptin receptor deficiency. However, in most cases, genes involved in weight gain do not directly cause obesity but they increase the susceptibility to fat gain in subjects exposed to a specific environment. Both genetic and environmental factors promote a positive energy balance which cause obesity. The relative inefficiency of self-adapting energy intake to energy requirements is responsible for fat gain in predisposed individuals. The role of the environment in the development of obesity is suggested by the rapid increase of the prevalence of obesity accompanying the rapid changes in the lifestyle of the population in the second half of this century. Early experiences with food, feeding practices and family food choices affect childrens nutritional habits. In particular, the parents are responsible for food availability and accessibility in the home and they affect food preferences of their children. Diet composition, in particular fat intake, influences the development of obesity. The high energy density and palatability of fatty foods as well as their less satiating properties promotes food consumption. TV viewing, an inactivity and food intake promoter, was identified as a relevant risk factor for obesity in children. Sedentarity, i.e. a low physical activity level, is accompanied by a low fat oxidation rate in muscle and a low fat oxidation rate is a risk factor of fat gain or fat re-gain after weight loss. Conclusion Further research is needed to identify new risk factors of childhood obesity, both in the genetic and environmental areas, which may help to develop more effective strategies for the prevention and treatment of obesity.

Long-Term Effects of Childhood Obesity on Morbidity and Mortality

Obesity tracks from childhood into adulthood, and the persistence of obesity rises with age among obese children. Early onset obesity was suggested as a risk factor for morbidity and mortality later in life. In both sexes, rates of diabetes, coronary heart disease, atherosclerosis, hip fracture and gout were increased in those who were overweight as adolescents. Especially in females, obesity at late adolescence was associated with several and relevant psychosocial consequences in adulthood. Finally, a higher mortality risk for all causes of death, especially atherosclerotic cerebrovascular disease and colorectal cancer, was demonstrated in males but not in females who were overweight during high school years. Although the persistence of excess adiposity from childhood to adulthood is a morbidity risk factor, it is not known if total body fat or body fat distribution is the main factor responsible. In particular, a specific role for the intra-abdominal adipose tissue (IAAT) in childhood, independently from that of total body fat, on morbidity risk in adulthood was not demonstrated yet. The association between childhood obesity and adult morbidity and mortality strongly suggests that a more effective prevention and treatment of childhood obesity should be pursued.

Metabolic syndrome in obese Caucasian children : prevalence using WHO-derived criteria and association with nontraditional cardiovascular risk factors

Objective:Studies on the prevalence of metabolic syndrome (MS) in European obese children using child-based criteria are scanty. Moreover, it is unknown if nontraditional cardiovascular disease (CVD) risk factors are associated with the MS at this early age in these subjects.Design and subjects:We studied the prevalence of the MS in 588 Caucasian obese children and adolescents by devising a World Health Organization derived definition and child-specific criteria, whose deviation from normalcy was based on an age, sex, and ethnically comparable control group of 1363 subjects. In a subgroup of 206 obese children, we investigated the association of the MS with nontraditional CVD risk factors.Measurements:Fasting blood samples for glucose and lipids measurements were taken in both control and obese children. In addition, the obese children underwent an oral glucose tolerance test. In the subgroup of 206 obese children, albumin excretion rate , plasma uric acid, fibrinogen, plasminogen activator inhibitor type 1(PAI-1), C-reactive protein, interleukin 6 and white blood cells were also measured.Results:The prevalence of MS was 23.3%. A similar prevalence of 23% of MS was recorded in the subgroup of 206 obese children in whom measurements of nontraditional CVD risk factors were available. After adjustment for the degree of obesity, subjects with MS had significantly higher uric acid (6.6±0.23 vs 6.1±0.12 mg/dl, P<0.0001) and PAI-1 plasma concentrations (231.4±25.50 vs 214.3±12.96 ng/ml, P<0.05) and a higher frequency of microalbuminuria (37 vs 20%, P<0.05) than those without MS. Microalbuminuria, uric acid and PAI-1 explained 10.6% of the variance of MS.Conclusion:Approximately, a quarter of Caucasian obese children have the MS. The association of MS with several nontraditional risk factors for CVD early in life suggests a heightened CVD risk in these individuals.

Relationship between physical inactivity and adiposity in prepubertal boys

OBJECTIVE To study the relationship between the energy expenditure for activity (EEAct), the level of activity and adiposity in a group of 9-year-old boys (n = 28) with different body composition (body weight, 38 +/- 10 kg [range, 23 to 66 kg]; fat mass, 23% +/- 10% [range, 8% to 42%]). METHODS Total energy expenditure (TEE) was measured by means of the heart-rate monitoring method. EEAct was calculated as TEE-(REE+0.1 TEE), where REE is the postabsorptive resting energy expenditure and 0.1 TEE corresponds to the postprandial thermogenesis (approximately 10% of TEE). RESULTS TEE, REE, and EEAct were 9388 +/- 1859, 5154 +/- 642, and 3295 +/- 1356 l J/day, respectively. Daily time devoted to sedentary and nonsedentary activities averaged 290 +/- 155 minutes (range, 69 to 621) and 534 +/- 150 minutes (range, 180 to 783), respectively. Time spent on sedentary activities was directly proportional to fat mass percentage (r = 0.46; p < 0.05). It was the only variable, among the free-living physical-activity [EEAct, TEE/(REE+0.1 TEE) ratio, time spent in nonsedentary and sedentary activities] variables, which remained significantly in the multiple step-down regression analysis final equation (r = 0.46; p < 0.05). CONCLUSIONS The positive relationship between adiposity and time spent on sedentary activities in 9-year-old boys suggests the importance of the role played by muscular activity, at least in the maintenance of obesity in childhood. Prepubertal children should be encouraged to spend less time on sedentary activities to treat and prevent their obesity.

Obesity and Inflammation: Evidence for an Elementary Lesion

In obesity, an inflammatory process of the adipose tissue has been hypothesized; however, direct evidence for a tissue lesion is still lacking. Macrophage infiltration in the adipose tissue of obese individuals seems to be proven, but other alterations of the tissue have not been demonstrated. Moreover, in humans it has not been clarified whether inflammation is an early characteristic of obesity, because no data from obese children are available. In the present study, we assessed the inflammatory involvement of the adipose tissue and identified the elementary “inflammatory” lesion in a group of obese children. The study of children gives us the chance to investigate adipose tissue during early phases of obesity. In all the obese subjects, ultramicroscopic analysis of the adipose tissue demonstrated inflammatory involvement, and the extent of the lesions seemed to depend on the SD score of body mass index. The elementary lesion is a microgranuloma, with fragments of adipocytes, that evolves to fibrosis. Macrophages (and less frequently, lymphocytes or granulocytes) were found in perivascular positions. The lesions were not found in nonobese children. Our study proved that an “inflammatory” process exists in the adipose tissue of obese children, confirming previous findings in animals and obese adults and demonstrating that it is an early alteration in humans. However, the accumulation of macrophages was just one of the components of the inflammatory lesion, which also involved adipocyte degeneration, fibrosis, and, to a lesser extent, granulocyte/lymphocyte accumulation. The finding of fragments of adipocytes in the elementary lesion suggests that, at the beginning of the process, adipocytes may degenerate and that the materials generated by this process can recruit macrophages and other leukocytes. These preliminary results suggest that additional studies should be designed to clarify the cause of adipocyte fragility in obese children.

Waist circumference as a predictor of cardiovascular and metabolic risk factors in obese girls

Objectives: (a) to explore the relationship between waist circumference and certain cardiovascular risk factors in a group of girls; and (b) to assess the clinical relevance of waist circumference in identifying girls with higher cardiovascular risk across puberty.Subjects and methods: One-hundred and fifty-five overweight or obese girls aged 5–16 y were recruited. Overweight and obesity were defined on the basis of BMI, according to Cole.Results: Waist circumference was significantly correlated with plasma insulin (r=0.43; P<0.001), systolic blood pressure (r=0.22; P=0.007) and IRHOMA (r=0.40; P<0.001). A multivariate linear correlation analysis showed that, when adjusted for age and Tanner stage, waist circumference was significantly associated with plasma insulin (r 2=0.23; P<0.01), IRHOMA (r 2=0.17; P<0.02), systolic and diastolic blood pressure (r 2=0.20; P=0.006 and r 2=0.32; P<0.001, respectively). A logistic regression analysis, using IRHOMA as the dependent variable, showed that waist circumference was a significant independent risk factor of insulin resistance (IRHOMA≥2.6) in this group of girls (OR 1.10; 95% CI 1.03–1.18; P=0.003), independently of their age and Tanner stage.Conclusions: Waist circumference of these girls was independently associated with certain cardiovascular risk factors, in particular insulin resistance and diastolic blood pressure, independently of age and Tanner stage. Thus suggesting that waist circumference may be reasonably included in clinical practice as a simple tool that may help to identify sub-groups of obese girls at higher metabolic risk across puberty.

Distribution of food intake as a risk factor for childhood obesity.

OBJECTIVE: The purpose of our study was to assess the relationship between nutrient intake, partitioning of food intake, parents’ overweight and adiposity in a group of children.SUBJECTS: 530 7–11-year-old children: 278 males, 252 females.METHODS: Energy intake, nutrient intake and percentage distribution of the intake of energy among the different meals were assessed by means of diet history. Body composition was obtained by measuring skinfold thickness.RESULTS: We identified the relationship between the childrens adiposity and their parents’ body mass index (BMI) mother: r=0.12, P<0.01; father: r=0.13; P<0.01), carbohydrate (r=−0.15, P<0.001) and fat intake (r=0.14, P<0.002), and the proportion of energy taken at dinner (r=0.1, P<0.05). A multiple regression analysis was run with a stepwise procedure using relative adiposity as the dependent variable and parents’ BMI, dinner intake (percentage of energy intake), EI/BMR ratio (an index of energy intake validity), and sex (dummy variable) as independent variables. All the independent variables, except percentage of fat intake, were included in the final model. The equation was able to explain ≈19% (R=0.44, P<0.001) of inter-individual fat mass percentage variability.CONCLUSIONS: Diet composition did not contribute to explain the childrens adiposity when the parents’ overweight (BMI) was taken into account. However, the percentage distribution of the intake of energy among the different meals, particularly at dinner, contributed to explain inter-individual variance of fatness in children of both sexes.