Resolution of metabolic syndrome and related metabolic disorders after bariatric surgery: comparison of sleeve gastrectomy and gastric bypass.

BACKGROUND: The effects of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) on metabolic syndrome (MS) in morbidly obese patients have not been well studied. OBJECTIVE: To compare the effectiveness of LSG and LRYGB in Chinese morbidly obese patients with MS. SETTING: University Hospital, China. METHODS: Patients who underwent LRYGB or LSG surgery and had completed at least 1 year of follow-up were retrospectively reviewed. Bariatric and metabolic outcomes in the 2 groups were compared. Univariate and multivariate analyses were performed to identify the predictors of MS remission. RESULTS: Of the 176 patients enrolled in this study, 79 underwent LSG and 97 underwent LRYGB. Eighty-three met 3 of the International Diabetes Federation criteria for diagnosis of MS, 69 met 4 of the criteria, and 24 met 5 of the criteria. At 1 year after bariatric surgery, 79% of patients achieved remission of MS. In both LSG and LRYGB groups, the number of MS criteria met by patients decreased significantly after surgery. The MS remission rate was not significantly different between the 2 groups (74.7% in LSG versus 82.5% in LGB; P = .21). In LSG patients, there was no significant decrease in blood pressure or increase in the high-density lipoprotein cholesterol at 1 year. On logistic regression analysis, younger age, lower body mass index, and lower homeostatic model of assessment-insulin resistance were independently associated with MS remission at 1 year after surgery. Both groups showed satisfactory and comparable weight loss (percentage of excess weight loss: 71.7% in LSG versus 74.4% in LRYGB). No surgery-related mortality occurred. CONCLUSIONS: Both LSG and LRYGB are feasible, safe, and effective in Chinese obese patients with MS. LSG seems to be inferior to LRYGB with regard to control of hypertension and high-density lipoprotein cholesterol.

Effects of Laparoscopic Roux-en-Y Gastric Bypass on Chinese Type 2 Diabetes Mellitus Patients with Different Levels of Obesity: Outcomes After 3 Years' Follow-Up.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been proven to be effective on treating type 2 diabetes mellitus (T2DM) in severely obese patients, but whether LRYGB surgery should be performed in obese class I patients is controversial. MATERIALS AND METHODS: A retrospective study of 3-year bariatric and metabolic outcomes in different obese class T2DM patients who underwent LRYGB was conducted to compare the effectiveness of LRYGB in obese class I patients with that in obese class II/III patients in a Chinese T2DM population. RESULTS: Totally, 58 patients with class I obesity and 45 patients with class II/III obesity were enrolled in this study. Major complications included two cases of incomplete intestinal obstructions and one anastomotic leak. The remission rates of T2DM were 70.6% in obese class I group and 77.8% in obese class II/III group at 1 year after surgery and 55.6 versus 64.3% at 3 years (all P > 0.05). Logistic regression analysis showed that higher waist circumference, lower fasting plasma glucose, and higher FCP at 2 h of OGTT were independently associated with diabetes remission at 1 year after surgery. At 1 year and thereafter, the percentage of excess weight loss was significantly greater in obese class II/III patients. At 3 years, body mass index was not significantly different between the two groups, and the obese class I patients had high recurrence rates of hypertension and hyperuricemia. CONCLUSIONS: LRYGB surgery is feasible, safe, and effective in Chinese obese class I patients with T2DM.

The Role of Wnt/ß-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

Temporal lobe epilepsy is one of the most common clinical neurological disorders. One of the major pathological findings in temporal lobe epilepsy is hippocampal sclerosis, characterized by massive neuronal loss and severe gliosis. The epileptogenesis process of temporal lobe epilepsy usually starts with initial precipitating insults, followed by neurodegeneration, abnormal hippocampus circuitry reorganization, and the formation of hypersynchronicity. Experimental and clinical evidence strongly suggests that dysfunctional neurogenesis is involved in the epileptogenesis. Recent data demonstrate that neurogenesis is induced by acute seizures or precipitating insults, whereas the capacity of neuronal recruitment and proliferation substantially decreases in the chronic phase of epilepsy. Participation of the Wnt/ß-catenin signaling pathway in neurogenesis reveals its importance in epileptogenesis; its dysfunction contributes to the structural and functional abnormality of temporal lobe epilepsy, while rescuing this pathway exerts neuroprotective effects. Here, we summarize data supporting the involvement of Wnt/ß-catenin signaling in the epileptogenesis of temporal lobe epilepsy. We also propose that the Wnt/ß-catenin signaling pathway may serve as a promising therapeutic target for temporal lobe epilepsy treatment.

The apolipoprotein CIII enhancer regulates both extensive histone modification and intergenic transcription of human apolipoprotein AI/CIII/AIV genes but not apolipoprotein AV.

The apolipoprotein (apo) AI/CIII/AIV/AV cluster genes are expressed at different levels in the liver and intestine. The apoCIII enhancer, a common regulatory element, regulates the tissue-specific expression of apoAI, apoCIII, and apoAIV but not apoAV. To study this regulation at the chromatin level, the histone modifications and intergenic transcription in the human apoAI/CIII/AIV/AV cluster were investigated in HepG2 and Caco-2 cells and in the livers of transgenic mice carrying the human gene cluster constructs with or without the apoCIII enhancer. We found that both the promoters and the intergenic regions of the apoAI/CIII/AIV genes were hyperacetylated and formed an open subdomain that did not include the apoAV gene. Hepatic and intestinal intergenic transcripts were identified to transcribe bidirectionally with strand preferences along the cluster. The deletion of the apoCIII enhancer influenced both histone modification and intergenic transcription in the apoAI/CIII/AIV gene region. These results demonstrate that the apoCIII enhancer contributes to the maintenance of an active chromatin subdomain of the apoAI/CIII/AIV genes, but not apoAV.

[Change of the chromosome conformation of human alpha-globin gene locus in transgenic mice].

OBJECTIVE: To establish chromosome conformation capture (3C) strategy and to use this method for exploring the effect of chromosome conformation on human alpha-globin gene expression in the human alpha-globin transgenic mouse. METHODS: Homozygous human alpha-globin transgenic male mouse was crossed with KM female mouse. The 14.5-day post-coitum (dpc) embryos were used for the isolation of fetal liver and fetal brain cells. Homogeneous single-cell suspension was treated with formaldehyde to crosslink the chromatin conformation in the nuclear. The cross-linked chromatin compound was digested with Nco I and then ligated with T4 DNA ligase. The ligated compound was reversely cross-linked and then the ligated genomic DNA was purified for PCR analysis. The primers were designed along the two sides of cut and ligated sites. Semi-quantitative PCR was used to analyze the chromosome conformation of the whole human alpha-globin gene locus in fetal liver and fetal brain cells. RESULTS: When HS40 fragment was used as the fixed fragment, in fetal brain cells, the ligation frequencies of HS40 fragment with other fragments were decreased as the linear distances to HS40 fragment were increasing; while in fetal liver cells, two active genes (alpha1 and alpha2) fragments showed higher ligation frequencies with HS40 fragment than other fragments. However, the fragment containing an inactive gene (xi) displayed the comparable low ligation frequency as that in fetal brain. When alpha2 fragment was used as the fixed fragment, similarly, in fetal brain cells the ligation frequencies of alpha2 fragment with other ones were decreased as the linear distances increasing; when in fetal liver cells, it showed higher ligation frequencies with two upstream regulatory elements (HS 40 and 33). However, it showed a little bit lower ligation frequency with another two upstream regulatory elements (HS10 and 8) than those in fetal brain. CONCLUSION: In fetal liver cells, the distant regulatory elements are in close proximity to the downstream of the expressed globin genes through looping out, the interval region; however, in fetal brain, they were not in vicinity to the expressed globin genes.

HS-48 alone has no enhancement role on the expression of human alpha-globin gene cluster.

To investigate the in vivo function of the newly defined DNase I hypersensitive site HS-48 on the whole human alpha-globin gene cluster, the region containing all the other known 5 hypersensitive sites HS-4 to HS-40 was deleted from a 117 kb bacterial artificial chromosome clone bearing the whole human alpha-globin gene cluster. Transgenic mice were generated from this construct. The RNase protection assays showed that with HS-48 left and all the other 5 hypersensitive sites deleted, the expression of human alpha-like globin genes was completely silenced in embryonic, fetal and adult stages in all tissues. This finding indicates that HS-48 alone has no enhancer activity on the expression of human alpha-like globin genes, and that the region of HS-4 to HS-40 already contains all the upstream cis-elements needed for regulating human alpha-like globin genes.

A conserved, extended chromatin opening within alpha-globin locus during development.

Histone modifications play an important role in eukaryotic gene regulation. However, the dynamic alteration of histone modification during development is poorly understood. In addition, the relationship between histone modification and globin gene switching remains unclear. Here, we assessed the dynamic pattern of histone modification (H3 acetylation, H4 acetylation, H3 K4 methylation, and H3 K79 methylation) along the murine alpha-globin locus, as well as along the human alpha-globin locus in transgenic mice, during globin gene switching in vivo. During the switching, histone modification at embryonic zeta-gene and fetal/adult alpha-genes displayed different developmental patterns. The level of histone modification at zeta-gene was developmentally regulated, in accordance with the level of zeta-gene expression, whereas the alpha-genes kept high level of histone modification at both developmental stages, regardless of their expression levels. Histone deacetylase inhibition selectively increased acetylation at the inactive zeta-gene in fetal livers, although it did not reactivate the gene expression. More importantly, an obvious increasing of histone modification level at major regulatory elements and fetal/adult alpha-genes was observed during the switching, suggesting that a conserved, extended chromatin opening within the locus occurs during globin gene switching.

Opening the chromatin for transcription.

Eukaryotic genomes are packaged into a dynamic hierarchy chromatin structure. In such a particular context, the transition from a repressed compacted chromatin to a rather extended fiber is necessary for transcription. The chromatin opening includes three events, the initial factor getting access to nucleosome DNA, local chromatin opening mediated by activator/coactivator, and transcription associated with extensive chromatin opening. Chromatin dynamics, which is DNA sequence dependent, and also occurs in condensed fiber, provides the opportunity for activators binding to DNA. Coactivators recruited by the activator open the chromatin locally. However, it appears that genes adopt distinct chromatin opening mechanisms according to whether the gene is induced expression, developmental and tissue-specific expression, or constitutive expression. In contrast to transcription initiation-related local chromatin opening, large scale of chromatin opening is associated with a functional enhancer as well as high transcription rate. How the transcription initiated from an enhancer or enhancer like modules, i.e. intergenic transcription, conducts the extensive chromatin opening is discussed. A model for long-range interaction that non-coding transcripts from enhancers may promote efficient communication with promoters is proposed.

Chromatin structure and transcriptional regulation of the beta-globin locus.

Chromatin structure plays a critical role in eukaryotic gene transcriptional regulation. The beta-globin locus provides an ideal system within which to study the interplay between chromatin structure and transcriptional regulation. The process of beta-globin locus activation is remarkably intricate and involves at least two distinct events: chromatin opening and gene activation. Great progress has been made in recent years in understanding how locus control regions confer high-level expression to linked genes. Current interest focuses on some special events, including formation of locus control region hypersensitivity sites, ATP-dependent chromatin remodeling, localized H3 hyperacetylation, and intergenic transcription, which link chromatin and beta-globin locus regulation. These events, and their possible molecular bases, are summarized together with speculations concerning their connections.