Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-alpha). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-alpha on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% (P < 0.05) increase in plasma adiponectin and a 45% (P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% (P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-alpha (P < 0.01) and IL-6 plus its soluble receptor (P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.

BACKGROUND: Previous studies have indicated that the secretion of the intestinal satiety hormone glucagon-like peptide-1 (GLP-1) is attenuated in obese subjects. OBJECTIVE: To compare meal-induced response of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in obese and lean male subjects, to investigate the effect of a major weight reduction in the obese subjects, and to look for an association between these hormones and ad libitum food intake. METHOD: Plasma concentrations of intestinal hormones and appetite sensations were measured prior to, and every 30 min for 180 min after, ingestion of a 2.5 MJ solid test meal. Gastric emptying was estimated scintigraphically. An ad libitum lunch was served 3 h after the test meal. SUBJECTS: Nineteen non-diabetic obese (body mass index (BMI) 34.1 ± 43.8 kgam 2 ) and 12 lean (BMI 20.4 ± 24.7 kgam 2 ) males. All obese subjects were re-examined after a mean stabilised weight loss of 18.8 kg (95% CI 14.4 ± 23.2). RESULTS: Total area under the GLP-1 response curve (AUC total, GLP-1 ) was lower in obese before and after the weight loss compared to lean subjects (P`0.05), although weight loss improved the response from 80 to 88% of that of the lean subjects (P 0.003). The GIP response was similar in obese and lean subjects. However, after the weight loss both AUC total, GIP and AUC incremental, GIP were lowered (P`0.05). An inverse correlation was observed between AUC incremental, GIP and energy intake at the subsequent ad libitum meal in all groups. In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r 2 0.67, P 0.001). CONCLUSION: Our study con®rmed previous ®ndings of a reduced postprandial GLP-1 response in severely obese subjects. Following weight reduction, GLP-1 response in the obese subjects apparently rose to a level between that of obese and lean subjects. The data suggests that postprandial insulin and GIP responses are key players in short-term appetite regulation.

Objective: To study the association between anthropometric and metabolic parameters as well as the effect of weight loss on plasma levels of the adipose tissue-derived cytokines interleukin-8 (IL-8), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) in abdominal obese men. Subjects: Nineteen obese (mean body mass index (BMI): 38:6^0:6 kg=m 2 ) and ten lean men (mean BMI: 23:4^0:4 kg=m 2 ) were included in the study. The obese subjects received a 4.2 MJ/day diet for 8 weeks, followed by 8 weeks on energy restriction (6.2 MJ/day) and 8 weeks on a weight-maintenance diet. Measurements: A dual energy X-ray absorptiometry (DEXA)-scan was performed to estimate body composition. Plasma levels of IL-8, IL-6 and TNF-a were measured by a specific ELISA method. Insulin sensitivity was assessed by the homeostasis model assessment method (HOMA). Results: Plasma levels of IL-8 and IL-6 were 30-40% higher in obese as compared with lean subjects ðP , 0:05Þ; whereas no group difference in TNF-a was observed. During the intervention, obese subjects obtained a 30% reduction in fat mass ðP , 0:001Þ; fasting insulin ðP , 0:05Þ and HOMA ðP , 0:05Þ: Plasma levels of TNF-a and IL-6 were decreased by 25-30% ðP , 0:001Þ but IL-8 was increased by 30% ðP , 0:001Þ after weight loss. IL-8 and IL-6 were correlated with measures of insulin resistance, and changes in IL-6 but not IL-8 were correlated with the improvement in insulin sensitivity after weight loss. Conclusion: Plasma levels of IL-8 and IL-6 were found to be increased and were correlated with measures of insulin resistance in abdominal obese male subjects. Weight loss was associated with changes in the circulating levels of IL-8, IL-6 and TNF-a indicating that these cytokines are influenced by weight loss.

Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results. Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects. Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion. Energy intake was reduced by 727 kJ (95% confidence interval, 548-908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634-1091 kJ) compared with overweight subjects (487 kJ) (209-764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7-36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion. Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.

Little is known about common factors (e.g., macronutrients and energy supply) regulating the protein secretory function of adipose tissue. We therefore compared the effects of randomly assigned 10-week hypoenergetic (؊600 kcal/day) diets with moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content on circulating levels and production of proteins (using radioimmunoassays and enzyme-linked immunosorbent assays) from subcutaneous adipose tissue in 40 obese but otherwise healthy women. Similar results were obtained by the two diets. Body weight decreased by ϳ7.5%. The secretion rate of leptin decreased by ϳ40%, as did that of tumor necrosis factor-␣ (TNF-␣), and interleukin (IL)-6 and -8 decreased by 25-30%, whereas the secretion of plasminogen activator inhibitor 1 (PAI-1) and adiponectin did not show any changes. Regarding mRNA expression (by real-time PCR), only that of leptin and IL-6 decreased significantly. Circulating levels of leptin and PAI-1 decreased by 30 and 40%, respectively, but there were only minor changes in circulating TNF-␣, IL-6, or adiponectin. In conclusion, moderate caloric restriction but not macronutrient composition influences the production and secretion of adipose tissue-derived proteins during weight reduction, leptin being the most sensitive and adiponectin and PAI-1 the least sensitive. Diabetes 53: 1966 -1971, 2004 A dipose tissue secretes a number of proteins with auto-, para-, and endocrine actions, such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-6 and -8, plasminogen activator inhibitor 1 (PAI-1), leptin, and adiponectin (1,2). Little is known about the regulation of the protein secretory function of human adipose tissue except for leptin (3). The effect of energy restriction is of particular importance for obesity treatment (4). Dietary-induced weight loss normalizes plasma levels and adipose tissue gene expression of several adipocyte-derived proteins (5-12). Whether the same is true for protein secretion is unknown, except for TNF-␣ (5,10). Furthermore, the relative roles of loss of body fat, energy restriction per se, and changes in macronutrient supply are not known. It is also unknown which proteins are more or less sensitive to nutritional changes regarding their production by adipose tissue. These questions were investigated by studying the release of leptin, adiponectin, IL-6 and -8, TNF-␣, and PAI-1 in subcutaneous adipose tissue of 40 obese women before and after 10 weeks on moderate hypoenergetic diets with either low-fat/highcarbohydrate content or moderate-fat/moderate-carbohydrate content. RESEARCH DESIGN AND METHODSAll subjects participated in a European multicenter study termed NutrientGene Interactions in Human Obesity: Implications for Dietary Guidelines (NUGENOB, www.nugenob.com), which examines the interaction between hypoenergetic diets and genes. Our Swedish center included 40 obese women aged 21-49 years with a BMI of 30.9 -47.7 kg/m 2 who were otherwise healthy and free of regular medication, except 1 woman who was treated wit...

It is unclear whether postprandial blood glucose or insulin exerts a regulatory function in short-term appetite regulation in humans. The aim of this study was to investigate, by use of meta-analysis, the role of blood glucose and insulin in short-term appetite sensation and energy intake (EI) in normal weight and overweight participants. Data from seven test meal studies were used, including 136 healthy participants (ALL) (92 normal weight (NW) and 44 overweight or obese (OW)). All meals were served as breakfasts after an overnight fast, and appetite sensations and blood samples were obtained frequently in the postprandial period. Finally, an ad libitum lunch was served. Data were analysed by fixed effects study level (SL) metaregression analysis and individual participant data (IPD) regression analysis, using STATA software. In SL analysis, postprandial insulin response was associated with decreased hunger in ALL, NW and OW (P, 0·019), and with increased satiety in NW (P¼ 0·004) and lower subsequent EI in OW (P¼ 0·022). Multivariate IPD analysis showed similar associations, but only in NW for hunger, satiety and EI (P ,0·028), and in ALL for EI (P¼ 0·016). The only association involving blood glucose was the multivariate IPD analysis showing an inverse association between blood glucose and EI in ALL (P¼ 0·032). Our results suggest that insulin, but not glucose, is associated with short-term appetite regulation in healthy participants, but the relationship is disrupted in the overweight and obese. We conclude that the postprandial insulin response may be an important satiety signal, and that central nervous system insulin resistance in overweight might explain the blunted effect on appetite.

Macronutrients have a secondary role in changes in adipocyte gene expression after energy-restricted diets. The most striking alteration after energy restriction is a coordinated reduction in the expression of genes regulating the production of polyunsaturated fatty acids.

Aims/hypothesis: Adaptation to energy restriction is associated with changes in gene expression in adipose tissue. However, it is unknown to what extent these changes are dependent on the energy restriction as such or on the macronutrient composition of the diet. Methods: We determined the levels of transcripts for 38 genes that are expressed in adipose tissue and encode transcription factors, enzymes, transporters and receptors known to play critical roles in the regulation of adipogenesis, mitochondrial respiration, and lipid and carbohydrate metabolism. Two groups of 25 obese subjects following 10-week hypocaloric diet programmes with either 20-25 or 40-45% of total energy derived from fat were investigated. Levels of mRNA were measured by performing real-time RT-PCR on subcutaneous fat samples obtained from the subjects before and after the diets. Results: The two groups of subjects lost 7 kg over the duration of the diets. Ten genes were regulated by energy restriction; however, none of the genes showed a significantly different response to the diets. Levels of peroxisome proliferator-activated receptor γ co-activator 1α mRNA were increased, while the expression of the genes encoding leptin, osteonectin, phosphodiesterase 3B, hormone-sensitive lipase, receptor A for natriuretic peptide, fatty acid translocase, lipoprotein lipase, uncoupling protein 2 and peroxisome proliferator-activated receptor γ was