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Adiponectin Gene Expression and Plasma Values in Obese Women during Very-Low-Calorie Diet. Relationship with Cardiovascular Risk Factors and Insulin Resistance

Franco-Czech Laboratory for Clinical Research on Obesity (M.G., N.V., S.P., E.K., D.L., V.S.), French Institute of Health and Medical Research (Institut National de la Santé et d la Recherche Médicale U586) and 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; Unité de Recherches sur les Obésités Institut National de la Santé et d la Recherche Médicale U586 (M.G., N.V., D.L.), Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, 31403 Toulouse, France; Department of Sports Medicine and Obesity Unit (S.P., E.K., V.S.), 3rd Faculty of Medicine, Charles University, 100 00 Praha 10, Prague, Czech Republic; Department of Physiology (M.G.), University of Murcia, Murcia 30 002 Spain; and Institut National de la Santé et de la Recherche Médicale "Avenir" 3502 and Paris VI University (K.C.), Department of Nutrition, Hôtel-Dieu, Paris, France

Address all correspondence and requests for reprints to: Dominique Langin, Unité de Recherches sur les Obésités, Institut National de la Santé et de la Recherche Médicale U586, Bâtiment L3, CHU Rangueil, 31403 Toulouse Cedex 4, France. E-mail: langin{at}toulouse.inserm.fr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adiponectin, a newly discovered adipose-tissue-specific protein, is thought to be involved in the regulation of insulin action. The aim of the present study was to determine whether adiponectin contributes to the improvement in insulin sensitivity during very-low-calorie diet (VLCD). Biopsies of sc abdominal adipose tissue and blood sampling for analysis of plasma adiponectin and related hormones and metabolites were performed before and at the end of a 4-wk VLCD in 33 nonmorbidly obese women (body mass index, 34.4 ± 4.1 kg/m²). VLCD produced a decrease in weight (7.1 ± 0.4 kg) and in insulin and leptin levels and led to an improvement in insulin sensitivity. Adiponectin gene expression and plasma levels were not modified during calorie restriction. Before VLCD, we found negative correlations between plasma adiponectin and variables related to the metabolic syndrome. Adiponectin mRNA levels showed a negative correlation with lipoprotein a plasma values. The correlations observed before VLCD were not found after VLCD. The data suggest that adiponectin is related to the protection against the metabolic syndrome but is not involved in the regulation of VLCD-induced improvement of insulin sensitivity.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBESITY RESULTS FROM a chronic imbalance between energy intake and energy expenditure. This syndrome is commonly associated with increased risks of cardiovascular problems and metabolic abnormalities, including hypertension, hyperinsulinemia, insulin resistance, and type 2 diabetes (1). Adipose tissue is the major site for energy storage and disposal and is also implicated in glucose homeostasis. There is an increasing body of evidence that this tissue has a pivotal role, in concert with the central nervous system (2), not only in the regulation of energy homeostasis but also of whole-body insulin action. Hormones and cytokines produced by adipose tissue have a wide-ranging effects on food intake, energy expenditure, and carbohydrate and lipid metabolism. Of these cytokines, adiponectin (also called GBP-28, adipoQ, Acrp30, and ApM1) is a novel adipose tissue-specific protein that has structural homology to collagen VIII and X and complement factor C1q and circulates in human plasma at high levels. In contrast to other adipocytokines, the expression of adiponectin mRNA is reduced in obesity and in insulin resistant states in mice and humans (3, 4). Concentrations of plasma adiponectin correlate negatively with body mass index (BMI) and glucose, insulin, and triglyceride levels and positively with high-density lipoprotein-cholesterol level and insulin-stimulated glucose disposal (5). It has been suggested that adiponectin increases insulin sensitivity by increasing fat oxidation, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents in liver and skeletal muscle (6). This protein also inhibits the inflammatory processes that occur during the early phases of atherosclerosis. It suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production of macrophages (7).

Intentional weight loss improves many of the medical complications associated with obesity, including insulin resistance. Moreover, many of these beneficial effects have a dose-dependent relationship with the amount of weight lost and appear with weight loss of 5–10% of initial body weight (8). However, at present, the factors that play a physiological role in the enhanced insulin sensitivity produced by weight loss are largely unknown. Because of the metabolic action of adiponectin and its abundant expression in adipose tissue, this cytokine is a candidate factor for mediating the effects of weight loss on insulin resistance. The aim of the present study was therefore to determine whether adiponectin contributes to the improvement in insulin sensitivity observed during a very-low-calorie diet (VLCD) in obese women.

	Subjects and Methods

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Study subjects

Thirty-three obese women, 37 ± 6 yr old, participated in the study. Mean body weight and BMI were 95 ± 14 kg (range, 76–132 kg) and 34 ± 4 kg/m², respectively. All subjects were drug-free, and their weight had remained stable for at least 3 months before the beginning of the study. They all gave written informed consent before the experiments began. The studies were performed according to The Declaration of Helsinki and approved by the Ethical Committee of the 3rd Faculty of Medicine (Prague, Czech Republic).

Study protocol

Subjects were given a liquid diet for 4 wk (Gayelord-Diepal-NSA, Ville Franche-sur-Saone, France) with 3360 kJ/d energy content. The diet was consumed in four portions/d, each containing one fourth of the whole-day energy content. Subjects were instructed not to eat any other food and not to change their habitual physical activity during the course of the diet. They were viewed by a physician once a week. Measurements of clinical parameters and biopsies were performed 1–2 d before the beginning of the diet and at the end of the 4-wk period. Needle biopsies of sc abdominal adipose tissue (SCAAT) were performed in the morning in fasted state as described previously (9), and the samples were processed and frozen for further analysis.

Anthropometric measurements

Weight, height, waist and hip circumference, and sagittal diameter were measured. Skinfold measurements were done according to Parizkova (10). Body composition was assessed in fasting condition by dual-energy x-ray absorptiometry performed with a total body scanner (Hologic, Siemens, Erlangen, Germany) enabling quantification of fat mass, lean body mass, and total bone mineral content (11). Abdominal obesity was defined by a waist-to-hip ratio above 0.85 (12).

Oral glucose tolerance test (oGTT)

An oGTT was performed in the morning in fasted state. The subject was given 75 g glucose in water solution, and plasma samples were taken before the glucose intake and 2 h after the intake for determination of glucose and insulin (13).

Plasma level determinations

Plasma glucose was determined with a glucose-oxidase technique (Biotrol kit, Merck-Clevenot, Nogent-sur-Marne, France), and nonesterified fatty acid (NEFA) by an enzymatic procedure (Wako kit, Unipath, Dardilly, France). Plasma insulin concentrations were measured using RIA kits from Sanofi Diagnostics Pasteur (Marnes-la-Coquette, France). Plasma triglycerides and lipoprotein a [Lp(a)] were determined by spectrophotometry. Adiponectin and leptin plasma levels were determined using RIA kits from Linco Research (St. Louis, MO) according to the manufacturer’s recommendations.

Adipose tissue mRNA quantitation

RT was performed using random hexamers as primers and Thermoscript reverse transcriptase (Invitrogen, Cergy Pontoise, France) with 1 µg total RNA for each biopsy. Ten nanograms of cDNA were used as template for real-time PCR as recommended by the manufacturer. A set of primers was designed for adiponectin mRNA using the software Primer Express 1.5 (Applied Biosystems, Courtaboeuf, France). Real-time PCR was performed on a GeneAmp 7000 Sequence Detection System (Applied Biosystems). A standard curve was obtained using serial dilutions of human adipose tissue cDNA. A dissociation curve was generated at the end of the PCR cycles to verify that a single gene product was amplified. We used 18S ribosomal RNA as control to normalize gene expression using the Ribosomal RNA Control TaqMan Assay kit (Applied Biosystems).

Statistical analysis

Data are presented as mean ± SD. The paired Student’s t test was performed to analyze differences between before and during the 4-wk VLCD treatment. Pearson's product moment correlation coefficients were used to investigate the relationship between: adiponectin gene expression and plasma levels, and anthropometric and insulin sensitivity variables. All statistical analyses were carried out using SPSS for WINDOWS (release 8.0; SPSS Inc, Chicago).

	Results

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General characteristics

Table 1 contains clinical parameters of obese subjects (n = 33) before and at the end of a 4-wk VLCD. The treatment induced moderate weight loss (7% of initial body weight) and fat loss.

No change in SCAAT adiponectin mRNA levels determined by reverse transcription-quantitative PCR was found during VLCD. Individual variations in adiponectin mRNA levels are shown in Fig. 1. Mean levels of normalized adiponectin mRNA were 0.050 ± 0.026 and 0.050 ± 0.022 before and after VLCD, respectively.

View larger version (29K): [in this window] [in a new window]   FIG. 1. Individual variations in normalized adiponectin mRNA with VLCD

Table 2 shows hormonal and metabolic parameters of obese subjects before and during VLCD (plasma adiponectin levels, indexes of insulin sensitivity, and cardiovascular risk factors). Leptin levels decreased during VLCD. Most of the cardiovascular risk factors and the insulin resistance-related variables showed a significant change toward clinical improvement at the end of the diet. Glucose values remained unchanged. No significant differences were found in plasma adiponectin levels when comparing values before and after VLCD. Fig. 2 represents individual variations of plasma adiponectin concentrations with VLCD.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Individual variations in plasma adiponectin levels with VLCD. To convert adiponectin concentration to micromoles per liter, divide by 30.

In view of these results, we decided to investigate whether there were relationships between adipose tissue adiponectin mRNA and plasma protein levels and metabolic syndrome parameters. Pearson correlation procedures between adiponectin plasma values, gene expression, and anthropometric data showed an inverse correlation with obesity parameters (Table 3). Before the diet, plasma adiponectin was negatively associated to fasting triglyceride levels, NEFA, and to fasting and postprandial (2-h oGTT) glycemia. Significant correlations were also found between adiponectin mRNA and postprandial (oGTT) glucose and Lp(a) plasma values before VLCD. It is important to highlight that the significant correlations found between adiponectin and metabolic syndrome variables disappeared during 4-wk VLCD. No correlations were found between mRNA or plasma levels of adiponectin and insulinemia or insulin sensitivity indexes.

Relationships between SCAAT adiponectin gene expression, plasma values, and insulin sensitivity before and during 4-wk VLCD in high responders and low responders to the VLCD

No statistical differences were found in adiponectin gene expression and plasma levels between high responders (>6 kg weight loss) and low responders to VLCD. There were no changes in these parameters with weight loss in either group. Moreover, no relationships were found in any of the groups between adiponectin (plasma or mRNA) and insulin sensitivity variables.

Relationships between SCAAT adiponectin gene expression, plasma values, and insulin sensitivity before and during 4-wk VLCD in abdominal and femoral type of obesity

The group was divided into two subgroups, one with abdominal (n = 15) and one with femoral type of obesity (n = 14) considering abdominal obesity when waist-to-hip ratio was more than 0.85. No differences were found in adiponectin mRNA expression and plasma levels between the two groups, and there were no changes in these parameters with weight loss. However, an inverse correlation between SCAAT adiponectin gene expression and fasting insulin (r = -0.60; P = 0.031) was found in the femoral obesity group before VLCD (Fig. 3). At the end of VLCD, this correlation disappeared.

View larger version (13K): [in this window] [in a new window]   FIG. 3. Relationship between adiponectin gene expression in adipose tissue and fasting insulin values before VLCD in women with femoral type of obesity.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

In the present study, adiponectin was not associated to fasting insulin and insulin sensitivity indexes. However, we found that, in women with femoral obesity but not in those with a central pattern of obesity, there was a relationship between SCAAT adiponectin gene expression and plasma insulin levels. The lack of correlation between plasma insulin and adiponectin levels in this group of women suggests that adiponectin production from SCAAT had a limited influence on plasma levels. Indeed, no relationship was found between sc adipose tissue adiponectin mRNA quantity and plasma concentrations. Many authors defend the hypothesis that the adipose tissue depot-specific expression of adiponectin may influence the pattern of plasma adiponectin concentrations and subsequent disease risk. It has been shown that adipose tissue depots differ in the strength of their association with the adverse metabolic consequence of obesity. Secretion of adiponectin is higher in omental cells than in sc cells (22, 23). Further studies are needed to analyze changes in adiponectin gene expression in intraabdominal adipose tissue with weight loss and its relationship with protein plasma values.

The relationship between plasma adiponectin levels and metabolic syndrome variables suggests that adiponectin may play a protective role against the development of cardiovascular diseases. Indeed, BMI, percentage of fat mass, waist circumference, triglyceride, and NEFA plasma concentrations were inversely correlated to adiponectin plasma levels. Lp(a) has been considered as an important cardiovascular risk factor (24). It shows a positive correlation with age, low-density lipoproteins, and triglycerides. Serum levels of Lp(a) are influenced by genetic factors, dietary habits, lifestyle, and hormonal state, though the specific contribution of these factors in the final concentration of Lp(a) is still unknown (25). In this study, an inverse and significant correlation between adiponectin gene expression and Lp(a) plasma values has been shown. These results might suggest that adiponectin could be a modulator of Lp(a) expression.

During VLCD, a common nutritional intervention prescribed to obese subjects, most of the inverse correlations found between adiponectin and the different metabolic syndrome variables disappeared. These results, together with the lack of variation of adiponectin mRNA and plasma levels with VLCD suggest that adiponectin does not play a major role in the improvement of insulin sensitivity observed during moderate weight loss in nonmorbidly obese women. This statement disagrees with other studies that conclude that adiponectin is a novel biological explanation for the beneficial effect of body weight loss on reducing insulin resistance. These studies show variations of adiponectin mRNA (26) and plasma levels with weight loss (27, 28, 29, 30). The same studies report changes in fasting and oGTT plasma glucose levels. It has been postulated that adiponectin reduces plasma glucose without stimulating insulin secretion (4). Indeed, in our study, data indicate that adiponectin was inversely correlated to fasting and 2-h oGTT glucose plasma levels without finding a significant correlation with plasma insulin. Moreover, no change was found in basal and 2-h oGTT plasma glucose values with weight loss. This lack of change could partly explain the lack of variation in adiponectin plasma and SCAAT gene expression values during VLCD. In most of the reviewed studies (26, 27, 29, 30), the weight reduction was accomplished by gastric partition or bariatric surgery in morbidly obese subjects. It may be speculated that changes in some neurohormonal factors as a consequence of the surgery intervention, especially stomach factors such as ghrelin (29) or gut peptides such as gastrin and cholecystokinin, may be involved in the changes of SCAAT adiponectin gene expression found in these subjects (27). Finally, the extent of weight loss in our study (7% initial BMI) was lower than in the reported studies (15–36% initial BMI).

In conclusion, adiponectin gene expression in SCAAT and plasma levels is associated with variables of the metabolic syndrome in obese women. A protective role of adiponectin against cardiovascular risk factors is therefore suggested. However, the improvement in insulin sensitivity observed during VLCD is not associated and, therefore, cannot be related to a VLCD-induced modification of adiponectin gene expression and plasma level.

	Footnotes

 
This work was supported by Grants from the Grant Agency of the Ministry of Health (Czech Republic) IGA 4674-3/1998 and IGA 6836-3, by Research Program VZ-1 of the 3rd Faculty of Medicine, Charles University, Prague (MSMT 1112200001), by the French Ministry for Foreign Affairs (Barrande program), and by the Institut National de la Santé et d la Recherche Médicale ATC-nutrition Grant no. 4NU10G.

Abbreviations: BMI, Body mass index; Lp(a), lipoprotein a; NEFA, nonesterified fatty acid; oGTT, oral glucose tolerance test; SCAAT, sc abdominal adipose tissue; VLCD, very-low-calorie diet.

Received August 28, 2003.

Accepted October 22, 2003.

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