Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study

Abstract

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.

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

“…Disruption in ECM leads to marked metabolic dysregulation and failure to expand AT in both obese patients and experimental obesity (high fat diet and ob/ob knockout) 41. In the same way, AT reduction as induced by a body weight reduction programme was shown to result from modified ECM gene expression profile 42. In obese patients, body fat loss as a consequence of gastric bypass was associated with increased fibrosis in fat depots after a 3 month to 1 year post‐surgery period 43.…”

Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

“…Participant recruitment and clinical investigation Altogether 46 overweight or obese (BMI 28-40 kg/m 2 ) participants aged 40 to 70 years with impaired fasting glucose (fasting plasma glucose concentration 5.6-7.0 mmol/l) or impaired glucose tolerance (2 h plasma glucose concentration 7.8-11.0 mmol/l) and at least two other features of the metabolic syndrome according to the Adult Treatment Panel III criteria [28] were randomised to a diet-induced weight-reduction (n= 28) or control group (n= 18) as previously described [7]. Of these, 24 participants randomised to the weight-reduction and ten participants randomised to the control group, all matched for age, sex, BMI and the status of glucose metabolism, were included in the present study as previously described [9].…”

“…Lifestyle intervention, including weight loss, has been shown to improve insulin and glucose metabolism and to reduce abdominal obesity [4][5][6][7][8][9]. Moreover, individuals with the metabolic syndrome are at an increased risk of type 2 diabetes mellitus and cardiovascular diseases [10,11].…”

Association of sequence variations in the gene encoding insulin-like growth factor binding protein 5 with adiponectin

“…Studies III-IV: FUNGENUT and GENOBIN study We combined two previously published study populations, FUNGENUT 17 and GENOBIN, 24,25 to examine the associations between gene expression of IGFBP5 and adiponectin at baseline. The participants had impaired fasting glycemia, or IGT and at least two other features of the metabolic syndrome according to the National Cholesterol Education Program criteria: waist circumference 4102 cm (males), 488 cm (females); fasting serum triacylglycerol concentration X1.7 mmol l À1 ; fasting serum highdensity lipoprotein cholesterol o1.0 mmol l À1 (males), o1.3 mmol l À1 (females); blood pressure X130/80 mm Hg.…”

“…For this purpose we utilized baseline data from FUNGENUT and GENOBIN study populations at baseline. 17,24 The persons recruited to these studies had metabolic syndrome and impaired glucose metabolism similarly to that of the participants in the DPS. The mRNA concentrations of IGFBP5 and adiponectin were highly correlated in all subjects (Po0.001, r 2 ¼ 0.368) and in women (P ¼ 0.001, r 2 ¼ 0.425) (Figure 4).…”