Objective: Lifestyle and genetic factors interact in the development of obesity and the metabolic syndrome. The molecular mechanisms underlying the beneficial dietary modifications are, however, unclear. We aimed to examine the effect of the longterm moderate weight reduction on gene expression in adipose tissue (AT) and to identify genes and gene clusters responsive to treatment and thereby likely contributing to the development of the metabolic syndrome. Design: Randomized controlled and individualized weight reduction intervention. Subjects: Forty-six subjects with impaired fasting glycemia or impaired glucose tolerance and features of metabolic syndrome, aged 6077 years were randomized either to a weight reduction (WR) (n ¼ 28) or a control (n ¼ 18) group lasting for 33 weeks. Measurements: Oral and intravenous glucose tolerance tests and subcutaneous AT biopsies were performed before and after the intervention. Gene expression of AT was studied using microarray technology in subgroups of WR (with weight reduction X5%, n ¼ 9) and control group (n ¼ 10). The results were confirmed using quantitative PCR. Results: In the WR group, glucose metabolism improved. Moreover, an inverse correlation between the change in S I and the change in body weight was found (r ¼ À0.44, P ¼ 0.026). Downregulation of gene expression (Po0.01) involving gene ontology groups of extracellular matrix and cell death was seen. Such changes did not occur in the control group. The tenomodulin-gene was one of the most downregulated genes (À39716%, Po0.0001). Moreover, its expression correlated with insulin sensitivity (r ¼ À0.34, P ¼ 0.005) before the intervention and with body adiposity both before (r ¼ 0.42, P ¼ 0.007) and after (r ¼ 0.30, P ¼ 0.056) the intervention. Conclusion: Genes regulating the extracellular matrix and cell death showed a strong downregulation after long-term weight reduction. This likely reflects a new stable state at the molecular level in AT. Further studies are warranted to elucidate the mechanisms of these genetic factors.

Dietary carbohydrate modification with rye and pasta or oat, wheat, and potato differentially modulates the gene expression profile in abdominal subcutaneous adipose tissue, even in the absence of weight loss.

BACKGROUND AND OBJECTIVE:The short form (Glu 9 =Glu 9 ) of the 12Glu9 deletion polymorphism of the a 2B -adrenergic receptor gene was previously found to be associated with reduced basal metabolic rate in obese subjects. We investigated the effects of this polymorphism on changes in body weight in Finnish non-diabetic and type 2 diabetic subjects during a 10 y follow-up. DESIGN: Controlled 10 y follow-up study with baseline, 5 and 10 y examinations. SUBJECTS: A total of 126 non-diabetic control subjects and 84 newly diagnosed, middle-aged type 2 diabetic patients from eastern Finland participated. MEASUREMENTS: Anthropometric measurements, blood pressure, oral glucose tolerance test, plasma insulin, plasma Cpeptide and glycosylated hemoglobin A 1c . Genotypes were determined by polymerase chain reaction followed by agarose gel electrophoresis. RESULTS: No significant differences were found in the prevalence of the 12Glu9 deletion polymorphism between non-diabetic and type 2 diabetic subjects. The non-diabetic subjects with the Glu 9 =Glu 9 genotype had a greater increase in their mean body weight during 5 y follow-up than the non-diabetic subjects with other genotypes (changes in body weight 0.4 AE 5.7, 70.5 AE 6.4 and 3.4 AE 4.9% for the Glu 12 =Glu 12 , Glu 12 =Glu 9 and Glu 9 =Glu 9 genotypes, respectively, P ¼ 0.040 for the difference between the groups). Also, the trend for the increment of body weight was statistically significant in the non-diabetic subjects with the Glu 9 =Glu 9 genotype (P ¼ 0.012). The 12Glu9 polymorphism was not cross-sectionally or longitudinally associated with body weight in type 2 diabetic subjects. CONCLUSIONS: The genotype of two short alleles (Glu 9 =Glu 9 ) was associated with an increase in body weight among nondiabetic subjects.

SIVENIUS, KATARIINA, LEO NISKANEN, MARKKU LAAKSO, AND MATTI UUSITUPA. A deletion in the ␣ 2B -adrenergic receptor gene and autonomic nervous function in central obesity. Obes Res. 2003;11:962-970. Objective: We investigated the impact of a three-amino acid deletion (12Glu9) polymorphism in the ␣ 2B -adrenergic receptor gene on autonomic nervous function. The short form (Glu 9 /Glu 9 ) of the polymorphism has previously been associated with a reduced basal metabolic rate in obese subjects. Because autonomic nervous function participates in the regulation of energy metabolism, there could be a link between this polymorphism and autonomic nervous function. Research Methods and Procedures: Data of a 10-year follow-up study with 126 nondiabetic control subjects and 84 type 2 diabetic patients were used to determine the effects of the 12Glu9 polymorphism on autonomic nervous function. A deep breathing test and an orthostatic test were used to investigate parasympathetic and sympathetic autonomic nervous function. In addition, cardiovascular autonomic function was studied using power spectral analysis of heart rate variability. Results: No significant differences were found in the frequency of the 12Glu9 deletion polymorphism between nondiabetic and diabetic subjects. The nondiabetic men with the Glu 9 /Glu 9 genotype, especially those with abdominal obesity, had significantly lower total and low-frequency power values in the power spectral analysis when compared with other men. Furthermore, in a longitudinal analysis of 10 years, the decrease in parasympathetic function was greater in nondiabetic men with the Glu 9 /Glu 9 genotype than in the men with the Glu 9 /Glu 12 or Glu 12 /Glu 12 genotypes. Discussion: The results of the present study suggest that the 12Glu9 polymorphism of the ␣ 2B -adrenergic receptor gene modulates autonomic nervous function in Finnish nondiabetic men. In the nondiabetic men with the Glu 9 /Glu 9 genotype, the general autonomic tone is depressed, and vagal activity especially becomes impaired with time. Furthermore, this association is accentuated by central obesity.

OBJECTIVE: To investigate the independent and combined effects of the Trp64Arg polymorphism of the b b 3 -adrenergic receptor (b b 3 AR) gene and the (À3826) A?G polymorphism of the uncoupling protein 1 (UCP1) gene on body weight change in type 2 diabetic and non-diabetic control subjects during a 10 y follow-up study. DESIGN: Controlled 10 y follow-up study with baseline, 5 and 10 y examinations. SUBJECTS: 70 newly diagnosed, middle-aged type 2 diabetic patients and 123 non-diabetic control subjects from eastern Finland. MEASUREMENTS: Anthropometric measurements, blood pressure, oral glucose tolerance test, plasma insulin, plasma C-peptide and HbA 1c . Genotypes by polymerase chain reaction followed by enzymatic digestion. RESULTS: No signi®cant differences were found in the frequencies of the two polymorphisms between diabetic and control subjects. The polymorphisms were not cross-sectionally or longitudinally associated with body weight or BMI in diabetic or control subjects. When the diabetic and control subjects were analysed together, the change in the mean body weight was signi®cantly greater among the subjects with both polymorphisms (n 11) than among those with no polymorphisms (n 103; change in weight 6.5 AE 2.5% vs À0.2 AE 0.8%, P 0.036, and change in Body Mass Index 8.5 AE 2.6% vs 2.0 AE 0.8%, P 0.060, mean AE s.e.m.). CONCLUSIONS: The simultaneous existence of the two polymorphisms was associated with a tendency to gain weight suggesting a synergistic effect of these polymorphisms on body weight gain.