Villy Våge

Switch from stress response to homeobox transcription factors in adipose tissue after profound fat loss.

Background In obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified. Methodology/Principal Findings In order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16). Adipose tissue from lean healthy individuals was also analyzed (n = 13). Two different microarray platforms (AB 1700 and Illumina) were used to measure the differential gene expression, and the results were further validated by qPCR. Surgery reduced BMI from 53.3 to 33.1 kg/m2. The majority of differentially expressed genes were down-regulated after profound fat loss, including transcription factors involved in stress response, inflammation, and immune cell function (e.g., FOS, JUN, ETS, C/EBPB, C/EBPD). Interestingly, a distinct set of genes was up-regulated after fat loss, including homeobox transcription factors (IRX3, IRX5, HOXA5, HOXA9, HOXB5, HOXC6, EMX2, PRRX1) and extracellular matrix structural proteins (COL1A1, COL1A2, COL3A1, COL5A1, COL6A3). Conclusions/Significance The data demonstrate a marked switch of transcription factors in adipose tissue after profound fat loss, providing new molecular insight into a dichotomy between stress response and metabolically favorable tissue development. Our findings implicate homeobox transcription factors as important regulators of adipose tissue function.

Health-related quality of life after bariatric surgery: a systematic review of prospective long-term studies

Impaired health-related quality of life (HRQoL) is common in bariatric surgery candidates and is often one of the motivating factors for seeking bariatric surgery. Although many studies have reported changes in HRQoL after bariatric surgery, few are long-term prospective studies and no systematic review has been conducted. A systematic database search identified studies reporting HRQoL preoperatively and≥5 years after bariatric surgery. Change in HRQoL over time was the outcome variable, divided into primary and secondary outcomes. Seven prospective cohort studies met the inclusion criteria. Eight HRQoL measures and 6 surgical methods were identified. Long-term follow-up time ranged from 5-10 years, sample sizes from 44 to 655 patients, and follow-up rates from 61% to 92%. None of the 7 studies were randomized controlled trials, and only 2 studies used control groups. Six of 7 studies showed statistically significant improvements in all of the primary outcomes, and 1 study showed statistically significant improvements in 1 of 2 primary outcomes. Of the statistically significant HRQoL improvements, 92% were clinically meaningful. Peak improvements in primary HRQoL outcomes were typically observed during the first years of follow-up, followed by a gradual decline that seemed to stabilize 5 years postoperatively. Long-term HRQoL scores typically remained improved relative to preoperative scores but were somewhat below population norm scores. In conclusion, while bariatric surgery candidates reported impaired HRQoL presurgically, their HRQoL improved considerably after bariatric surgery and much of the initial HRQoL improvements were maintained over the long term.

Jejunoileal bypass in the treatment of morbid obesity: a 25-year follow-up study of 36 patients.

Background: Induction of intestinal malabsorption by jejunoileal (JI) bypass was a widely performed procedure for morbid obesity in the 1970s.The purpose of this study was to evaluate the long-term results. Methods: A total of 36 patients underwent JI bypass from November 1971 to September 1976. At operation the median age was 33 years and median BMI 42 kg/m2. Shunt lengths varied between 45 and 60 cm. The present check-up of the 28 patients still alive included clinical examination, biochemical tests, bone density measurement and measurement of fecal fat excretion. Results: 10 patients (28%) had had their shunt reversed. With one exception these patients quickly regained weight, and 5 (50%) of them were dead. 23 patients with an intact JI shunt are alive, but 5 of them have had the shunt shortened due to weight gain.Their median age today is 56 years, and median BMI is 30. None of these patients were known to have coronary heart disease or diabetes mellitus at follow-up. Malabsorption of fat is still present. Blind loop syndrome, flatulence, foul fecal smell and diarrhea are the most troublesome long-term sequelae. Vitamin and mineral deficiencies are common. 2 of 21 patients (age 80 and 57 years) have osteoporosis. Conclusion: When the optimal shunt length for the individual patient is found, JI bypass maintains a substantially reduced weight for 25 years. Vitamin and mineral deficiencies are common, but no serious clinical deficiency states are seen.

Changes in obesity-related diseases and biochemical variables after laparoscopic sleeve gastrectomy: a two-year follow-up study

BackgroundTo evaluate changes in obesity-related diseases and micronutrients after laparoscopic sleeve gastrectomy (LSG).MethodsWe started the procedure in May 2007, and by December 2011, 117 patients could be evaluated for a two year follow-up. Comparisons of preoperative status with 12 and 24 months postoperative status were made for body mass index (BMI), obesity-related diseases and micronutrients.ResultsMajor complications included bleeding requiring transfusion at 5.1%, leak at 1.7% and abscess without a visible leak at 0.9%. Mean BMI was reduced from 46.6 (standard deviation (SD) 6.0) kg/m2 to 30.6 (SD 5.6) kg/m2 at two years, and resolution occurred for 80.7% of patients with type 2 diabetes, 63.9% with hypertension, 75.8% with hyperlipidemia, 93.0% with sleep apnea, 31.4% with musculoskeletal pain, 85.4% with snoring and 73.3% with urinary incontinence. Amenorrhea resolved in all premenopausal females. The proportion of patients with symptomatic gastroesophageal reflux disease increased from 12.8% to 27.4%. The prevalence of patients with low ferritin-levels increased, while 25-hydroxyvitamin D (25(OH)D) deficiency decreased postoperatively.ConclusionsLSG is an effective procedure for morbid obesity and obesity-related diseases, but the technique should be further explored particularly to avoid gastroesophageal reflux.

The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss

Background:Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown.Objective:To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes.Design:Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue.Subjects:A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss, 12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members and in silico promoter analysis based on microarray data.Results:There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As were expressed at the highest level in stromal–vascular fraction compared with adipocytes, but were downregulated in both fractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity. The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were strongly induced within 30 min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.

Anxiety, Depression and Health-Related Quality of Life after Jejunoileal Bypass: A 25-Year Follow-up Study of 20 Female Patients

Background: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s.The aim of this study was to investigate the long-term status for mental and physical health after weight loss induced by this operation. Methods: 20 female patients (age 48-80 y, BMI 23-75 kg/m2) were interviewed 25 years after JI bypass. The Hospital Anxiety and Depression Scale (HAD) and Short Form 36 (SF-36) were used. Scores from the Norwegian female population, and published scores for morbidly obese patients were used for comparison. An assessment was made on whether present demographic and clinical factors influenced the scores. Results: Anxiety and depression scores, and scores for physical functioning, bodily pain, vitality and mental health on the SF-36 were similar to scores in the Norwegian female population used for comparison. The scores from the patient sample were much better than scores published for morbidly obese patients, and implies that weight loss induced by the operation has been of great benefit on mental health and health-related quality of life. Anxiety and depression symptoms improved; however, being socially handicapped by the stools had a negative impact on HAD and SF-36 scores. Conclusion: These results suggest that 25 years after the JI bypass most of these patients have a similar level of mental and physical health as the general Norwegian female population. For individuals with bothersome side-effect(s) of the operation, a negative impact is seen.

Bone Mineral Density in Females after Jejunoileal Bypass: A 25-year Follow-up Study

Background: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s.The aim of this study was to investigate the long-term status of bone mineral density (BMD) after weight loss induced by this technique. Subjects and Methods: 18 female patients (age 48-79 y, BMI 23-43 kg/m2) had BMD measurements performed 25 years after JI bypass. Dual energy x-ray absorptiometry was used, and measured sites were the lumbar spine L2-L4, left femoral neck and total hip. Vitamin and mineral supplementation had not routinely been prescribed. An assessment was made on age-adjusted BMD values, and as to whether present BMD was related to present demographic and biochemical variables. Results: No significant reduction of BMD was found beyond that which was expected for age. BMD was inversely and separately related to age and body weight. The serum level of vitamin D was low in 45% of the patients, and inversely correlated to body weight and BMI. Alk phosphatase and parathyroid hormone were the best markers for low BMD. Conclusion: These results suggest that JI bypass has not been detrimental to bone density in females. We recommend, however, vitamin D and calcium supplements after malabsorptive procedures for morbid obesity.

Employment status and sick-leave following obesity surgery: a five-year prospective cohort study.

Background. Severe obesity is a risk factor for lower participation in paid work, but whether employment increases and sick leave decreases after obesity surgery is not well documented. Methods. We assessed 224 Norwegian patients with severe obesity (mean age: 40; mean BMI: 49; 61% female) regarding employment status (working versus not working) and the number of days of sick leave during the preceding 12 months, before and five years after obesity surgery (75% follow-up rate). Logistic regression analysis was used to study preoperative predictors of employment status after surgery. Results. There were no change in the employment rate over time (54% versus 58%), but the number of days of sick leave per year was significantly reduced, from a mean of 63 to a mean of 26, and from a median of 36 to a median of 4. Most of this change was attributable to patients with zero days of sick leave, which increased from 25% to 41%. Being female, older, having low education level, receiving disability pension and not being employed before obesity surgery were important risk factors for not being employed after obesity surgery. The type of obesity surgery, BMI and marital status were not useful predictors. Conclusions. Our findings suggest that undergoing obesity surgery is not associated with a higher rate of employment, although it may reduce the number of days of sick leave. Additional interventions are likely needed to influence the employment status of these patients. The significant preoperative predictors of not being employed in this study provide suggestions for further research.

Changes in adipose glucocorticoid metabolism before and after bariatric surgery assessed by direct hormone measurements

Increased intra‐adipose cortisol is thought to promote obesity, but few human studies have investigated intra‐adipose glucocorticoid hormones and none have demonstrated prospective changes with fat loss.

Cardiovascular risk factors in obese patients treated with jejunoileal bypass operation: a 25-year follow-up study

Objective Jejunoileal (JI) bypass was a widely performed surgical procedure for morbid obesity in the 1970s. The purpose of this study was to assess cardiovascular risk factors and mortality in patients 25 years or more after this operation. Material and methods All (n=36) patients operated on for obesity with JI bypass at Haukeland University Hospital between 1971 and 1976 were evaluated. Survivors (n=28) participated in a follow-up that included clinical examination and biochemical tests. Preoperative data were compared with data at 1 year (3 years) and 25 years. Causes of death were identified for the deceased. Results For the 23 patients alive with intact JI shunts at 25 years there was a statistically significant lowering of body mass index (BMI) (p<0.01), systolic blood pressure (p<0.05), diastolic blood pressure (p<0.001) and serum cholesterol (p<0.05) compared to before the operation. There was no statistically significant change in fasting blood glucose or serum triglyceride. The serum insulin level was normal in all but one (21/22) of the patients examined. Three out of 26 patients with intact JI shunts, and 5 out of 10 patients with reversed JI shunts, had died. Conclusion For patients with intact shunts there is a persistent reduction in body weight, serum cholesterol and blood pressure, and a reduced insulin resistance 25 years after JI bypass.