Sari Venesmaa

Adipose Tissue TCF7L2 Splicing Is Regulated by Weight Loss and Associates With Glucose and Fatty Acid Metabolism

We investigated the effects of obesity surgery-induced weight loss on transcription factor 7-like 2 gene (TCF7L2) alternative splicing in adipose tissue and liver. Furthermore, we determined the association of TCF7L2 splicing with the levels of plasma glucose and serum free fatty acids (FFAs) in three independent studies (n = 216). Expression of the short mRNA variant, lacking exons 12, 13, and 13a, decreased after weight loss in subcutaneous fat (n = 46) and liver (n = 11) and was more common in subcutaneous fat of subjects with type 2 diabetes than in subjects with normal glucose tolerance in obese individuals (n = 54) and a population-based sample (n = 49). Additionally, there was a positive correlation between this variant and the level of fasting glucose in nondiabetic individuals (n = 113). This association between TCF7L2 splicing and plasma glucose was independent of the TCF7L2 genotype. Finally, this variant was associated with high levels of serum FFAs during hyperinsulinemia, suggesting impaired insulin action in adipose tissue, whereas no association with insulin secretion or insulin-stimulated whole-body glucose uptake was observed. Our study shows that the short TCF7L2 mRNA variant in subcutaneous fat is regulated by weight loss and is associated with hyperglycemia and impaired insulin action in adipose tissue.

Lipoprotein subclass metabolism in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver. In addition, increased cholesterol content in the liver associates with NASH. Here we study the association of lipoprotein subclass metabolism with NASH. To this aim, liver biopsies from 116 morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, BMI 45.1 ± 6.1 kg/m2, 39 men and 77 women] were used for histological assessment. Proton NMR spectroscopy was used to measure lipid concentrations of 14 lipoprotein subclasses in native serum samples at baseline and after obesity surgery. We observed that total lipid concentration of VLDL and LDL subclasses, but not HDL subclasses, associated with NASH [false discovery rate (FDR) < 0.1]. More specifically, total lipid and cholesterol concentration of VLDL and LDL subclasses associated with inflammation, fibrosis, and cell injury (FDR < 0.1), independent of steatosis. Cholesterol concentration of all VLDL subclasses also correlated with total and free cholesterol content in the liver. All NASH-related changes in lipoprotein subclasses were reversed by obesity surgery. High total lipid and cholesterol concentration of serum VLDL and LDL subclasses are linked to cholesterol accumulation in the liver and to liver cell injury in NASH.

Desmosterol in human nonalcoholic steatohepatitis

Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 ± 8.1 years [mean ± standard deviation, SD], body mass index [BMI] 45.0 ± 6.1 kg/m2). Serum and liver levels of cholesterol precursors were measured with gas‐liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 ± 5.8 years, BMI 27.1 ± 4.0 kg/m2). Serum desmosterol levels and the desmosterol‐to‐cholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology (P = 0.002 and P = 0.003, respectively). Levels of serum and liver desmosterol correlated strongly (r = 0.667, P = 1 × 10−9), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver (P < 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels (P = 2 × 10−6) and the serum desmosterol‐to‐cholesterol ratio (P = 5 × 10−5) were associated with serum ALT in the population study. Conclusion: Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated. (Hepatology 2013;53:976–982)

Ketone body production is differentially altered in steatosis and non‐alcoholic steatohepatitis in obese humans

Levels of ketone bodies have been reported to be both increased and decreased in individuals with non‐alcoholic fatty liver disease. We investigated whether the metabolism of ketone bodies is different in simple steatosis and in non‐alcoholic steatohepatitis (NASH).

Genetic Risk Score Does Not Predict the Outcome of Obesity Surgery

BackgroundWe evaluated the benefit of using combined genetic risk score (GRS) of known single nucleotide polymorphisms (SNPs) for body mass index (BMI) and waist/hip ratio (WHR) in the prediction of weight loss and weight regain after obesity surgery.MethodsA total of 163 consecutive morbidly obese individuals undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in a single bariatric center in Finland were recruited. Fasting blood samples were drawn after 12 h of fasting before and 1 year after bariatric operation. Data for weight regain and medication were collected with a questionnaire after 3.1 ± 2.7 years (mean ± SD) follow-up. Nonalcoholic steatohepatitis (NASH) was diagnosed with liver histology. Twenty BMI- and 13 WHR-related SNPs were genotyped. Linear regression was used to identify factors predicting weight loss and weight regain.ResultsLower baseline BMI predicted greater decline in BMI (p = 0.0005) and excess weight loss (EWL) (p = 0.009). In the multiple linear regression analysis age and BMI, explained the variance of EWL during the first year while GRS, sex, fasting plasma glucose, serum insulin and NASH diagnosis did not have any effect. None of the baseline clinical variables explained BMI regain. The combined GRS did not associate with weight or BMI at baseline, with 1-year changes or with weight regain between 1 year and an average of 3.1 years follow-up.ConclusionsIn our study, we found that the genotype risk score does not predict weight loss after obesity surgery while lower baseline BMI predicted the greater weight loss.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss

Aims/hypothesisThe insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue.MethodsTo determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49).ResultsExpression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10−5) and the VLCD (p = 1 × 10−4). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10−22). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10−5), a known regulator of INSR exon 11 splicing.Conclusions/interpretationINSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.

Regulation of alternative splicing in human obesity loci.

Multiple obesity susceptibility loci have been identified by genome‐wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci.

Evaluation of the Effect of Bariatric Surgery-Induced Weight Loss on Knee Gait and Cartilage Degeneration

The objective of the study was to investigate the effects of bariatric surgery-induced weight loss on knee gait and cartilage degeneration in osteoarthritis (OA) by combining magnetic resonance imaging (MRI), gait analysis, finite element (FE) modeling, and cartilage degeneration algorithm. Gait analyses were performed for obese subjects before and one-year after the bariatric surgery. FE models were created before and after weight loss for those subjects who did not have severe tibio-femoral knee cartilage loss. Knee cartilage degenerations were predicted using an adaptive cartilage degeneration algorithm which is based on cumulative overloading of cartilage, leading to iteratively altered cartilage properties during OA. The average weight loss was 25.7±11.0 kg corresponding to a 9.2±3.9 kg/m2 decrease in body mass index (BMI). External knee rotation moment increased, and minimum knee flexion angle decreased significantly (p < 0.05) after weight loss. Moreover, weight loss decreased maximum cartilage degeneration by 5±23% and 13±11% on the medial and lateral tibial cartilage surfaces, respectively. Average degenerated volumes in the medial and lateral tibial cartilage decreased by 3±31% and 7±32%, respectively, after weight loss. However, increased degeneration levels could also be observed due to altered knee kinetics. The present results suggest that moderate weight loss changes knee kinetics and kinematics and can slow-down cartilage degeneration for certain patients. Simulation results also suggest that prediction of cartilage degeneration is subject-specific and highly depend on the altered gait loading, not just the patients weight.

Serum, liver and bile sitosterol and sitostanol in obese patients with and without NAFLD

Background and aims: Non-alcoholic fatty liver disease (NAFLD) associates with low levels of serum plant sterols in cross-sectional studies. In addition, it has been suggested that the hepatic sterol transport mechanisms are altered in NAFLD. Therefore, we investigated the association between serum, liver and bile plant sterols and sitostanol with NAFLD. Methods: Out of the 138 individuals (age: 46.3 ± 8.9, body mass index: 43.3 ± 6.9 kg/m², 28% men and 72% women), 44 could be histologically categorized to have normal liver, and 94 to have NAFLD. Within the NAFLD group, 28 had simple steatosis and 27 had non-alcoholic steatohepatitis. Plant sterols and sitostanol were measured from serum (n=138), liver (n=38), and bile (n=41). The mRNA expression of genes regulating liver sterol metabolism and inflammation was measured (n=102). Results: Liver and bile sitostanol ratios to cholesterol were higher in those with NAFLD compared to those with histologically normal liver (all P<0.022). Furthermore, liver sitostanol to cholesterol ratio correlated positively with histological steatosis and lobular inflammation (rs > 0.407, P<0.01 for both). In contrast, liver sitosterol to cholesterol ratio correlated negatively with steatosis (rs = −0.392, P=0.015) and lobular inflammation (rs = −0.395, P=0.014). Transcriptomics analysis revealed suggestive correlations between serum plant sterol levels and mRNA expression. Conclusion: Our study showed that liver and bile sitostanol ratios to cholesterol associated positively and liver sitosterol ratio to cholesterol associated negatively with liver steatosis and inflammation in obese individuals with NAFLD..