Insulin Resistance Is the Main Characteristic of Metabolically Unhealthy Obesity (MUO) Associated with NASH in Patients Undergoing Bariatric Surgery.

(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m2 (36-74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ2 (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ2 (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.

Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery.

Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m2. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.

A Long-Term Comparative Study Between One Anastomosis Gastric Bypass and Sleeve Gastrectomy.

BACKGROUND: One anastomosis gastric bypass (OAGB) has become increasingly accepted in bariatric surgery and meanwhile represents the third most common procedure worldwide. While it shows promising weight loss results and comorbidity resolution, questions about issues such as reflux or nutritional deficiencies (ND) persist in the long term. On the other hand, the most frequently performed sleeve gastrectomy (SG) has to accept growing criticism regarding long-term results and reflux issues. There is a particular lack of long-term comparative data for both procedures. This study presents our long-term experience. METHODS: We evaluated OAGB and SG patients retrospectively comparing for weight loss and resolution of comorbidities as well as perioperative and long-term complications in a follow-up period of 5 years. RESULTS: Nine hundred eleven OAGB and 241 SG were included in the study. OAGB had a shorter operation time and hospital stay. Overall complication rate did not differ in both groups. Ulcers were more frequent in OAGB (7.7% vs. 1.7%, p = 0.001), whereas insufficient weight loss (IWL)/weight regain (WR) proved to be more prevalent in SG (25.7% vs. 6.4%, p < 0.001). The same held true for reflux (17.8% vs. 8.3%, p < .001). On the other hand, ND were more common in OAGB (20.0% vs. 12.0%, p = 0.005). Revisional surgery was more often indicated after SG. Analysis by linear mixed model showed that OAGB achieved a lower BMI/higher loss of BMI. Improvement of T2DM (94.6% vs. 85.2%, p = 0.008) and sleep apnea (88.8% vs. 78.8%, p = 0.01) was superior in OAGB. CONCLUSIONS: OAGB had a superior effect on weight loss as well as improvement of T2DM and sleep apnea. Furthermore, long-term problems such as IWL/WR and reflux were more related to SG. On the other hand, a malabsorptive procedure such as OAGB showed a higher risk for ND. Our findings support the available data in the literature.

Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis.

OBJECTIVE: Obesity represents a growing health problem that is reaching pandemic dimensions and lacks effective cures, thus highlighting an urgent need for better mechanistic understanding and new therapeutic strategies. Unlike transcription, the function of translation in obesity has hardly been investigated. Here, we fill this knowledge gap by pinpointing a crucial function for gene regulation at the step of translation in diet-induced obesity. METHODS: We performed studies with human adipose tissue, high-fat-diet-induced obese mice and rats, CPEB4-knockout mice, and adipocyte lines. Cells were transfected with small-interfering RNAs that knockdown CPEB4. Transcriptome-wide identification and validation of CPEB4 targets in adipocytes were obtained by RNA-protein coimmunoprecipitation and high-throughput sequencing. The effect of CPEB4 depletion on high-fat-diet-induced dysbiosis was determined by 16S ribosomal-RNA gene sequencing and microbiome bioinformatics. RESULTS: We show that cytoplasmic polyadenylation element-binding protein 4 (CPEB4), which controls the translation of specific mRNAs by modulating their poly(A) tails, is highly expressed in visceral fat of obese but not lean humans and rodents (mice and rats), where it orchestrates an essential post-transcriptional reprogramming for aggravation of high-fat-diet-induced obesity. Mechanistically, CPEB4 overexpression in obese adipocytes activates the translation of factors essential for adipose tissue expansion (Cebpb, Stat5a) and adipocyte-intrinsic immune-like potential (Ccl2, Tlr4), as demonstrated by RNA-immunoprecipitation and high-throughput sequencing and experimentally validated in vivo. Consistently blocking CPEB4 production in knockout mice protects against diet-induced body weight gain and reduces adipose tissue enlargement and inflammation. In addition, the depletion of CPEB4 specifically in obese adipocytes using short hairpin RNAs decreases cell differentiation, lipid accumulation, and the proinflammatory and migratory capacity of macrophages. The absence of CPEB4 also attenuates high-fat diet-induced dysbiosis, shaping the microbiome composition toward a more beneficial profile, as shown by microbiome bioinformatics analysis. CONCLUSION: Our study identifies CPEB4 as a driver and therapeutic target to combat obesity.

Mouse Models of Nonalcoholic Steatohepatitis: Head-to-Head Comparison of Dietary Models and Impact on Inflammation and Animal Welfare.

A variety of dietary nonalcoholic steatohepatitis (NASH) mouse models are available, and choosing the appropriate mouse model is one of the most important steps in the design of NASH studies. In addition to the histopathological and metabolic findings of NASH, a sufficient mouse model should guarantee a robust clinical status and good animal welfare. Three different NASH diets, a high-fat diet (HFD60), a western diet (WD), and a cafeteria diet (CAFD), were fed for 12 or 16 weeks. Metabolic assessment was conducted at baseline and before scheduled sacrifice, and liver inflammation was analyzed via fluorescence-associated cell sorting and histopathological examination. Clinical health conditions were scored weekly to assess the impact on animal welfare. The HFD60 and WD were identified as suitable NASH mouse models without a significant strain on animal welfare. Furthermore, the progression of inflammation and liver fibrosis was associated with a decreased proportion of CD3+ NK1.1+ cells. The WD represents a model of advanced-stage NASH, and the HFD60 is a strong model of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. However, the CAFD should not be considered a NASH model.

The Role of Macrophage-Inducible C-Type Lectin in Different Stages of Chronic Liver Disease.

The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.

One Anastomosis Gastric Bypass-Mini-Gastric Bypass (OAGB-MGB) Versus Roux-en-Y Gastric Bypass (RYGB)-a Mid-Term Cohort Study with 612 Patients.

BACKGROUND: OAGB-MGB emerged as a standard procedure, albeit RYGB remains the most frequently performed gastric bypass. Comparative studies are scarce. METHODS: Prospectively collected data (July 2006 to November 2017) from a large sample size and adequate follow-up were analyzed using logistic regression and linear mixed models. Total weight loss (TWL) within the first 3 years was defined as primary outcome and duration of operation, perioperative, and late complications and comorbidity remission as secondary outcomes. RESULTS: Three hundred twenty-four OAGB-MGBs (age 42.51 ± 11.36 years, 74.69% females) presented with higher preoperative BMI (53.75 ± 6.51 kg/m2 vs. 44.53 ± 3.65 kg/m2, p < 0.0001) and higher comorbidity prevalence than 288 RYGBs (age 41.4 ± 10.04 years, 79.86% females). Duration of operation was 80.28 ± 20.31 min in OAGB-MGB and 103.36 ± 29.69 min in RYGB (p < 0.0001). Intraoperative complications (4.63% resp. 8.68%), early re-laparoscopy (0.62% resp. 0.69%), leakage (1.23% resp. 1.74%), internal hernias (IH) (0.32% resp. 3.85%), marginal ulcers (3.23% resp. 5.59%), gastroesophageal reflux (3.55% resp. 0.70%), and insufficient weight loss at 3 years (4.19% resp. 5.59 %) were comparable in OAGB-MGB resp. RYGB. Follow-up rates at 1 and 3 years declined from 76.71 to 42.86% (OAGB-MGB) resp. 79.15 to 50.00% (RYGB). TWL (OAGB-MGB, 36.18 ± 9.18%; RYGB, 33.8 ± 8.75%), malnutrition (OAGB-MGB, 4.19%; RYGB, 2.45%), and comorbidity remission 3 years postoperatively revealed comparable robust data. Anastomotic stenosis (1.94% resp. 14.69%) and dumping syndrome (3.55% resp. 6.64%) were less frequent in OAGB-MGB. CONCLUSIONS: TWL, malnutrition, and comorbidity remission 3 years postoperatively were comparable. Gastroesophageal reflux was less frequent after RYGB (p = 0.0729), whereas shorter operation times (p < 0.0001), less frequent stenosis (p < 0.0001), and dumping syndrome (p = 0.0018) were found in OAGB-MGB. Further RCTs are required.

Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

A New Physiologic Mouse Model of One Anastomosis Gastric Bypass.

BACKGROUND: One anastomosis gastric bypass (OAGB) is a modern metabolic operation that has been demonstrated to be a rapid, safe, and effective procedure. As for other bariatric operations, the mechanisms and long-term effects of this procedure remain largely unknown and are difficult to address in human studies. Here, we present a new physiologic mouse model for mechanistic and long-term investigations. METHODS: Six-week-old C57Bl/6 mice were fed a high-fat diet for 12 weeks and scheduled for OAGB or sham operation. Mice were observed for 2 weeks after the operation, and weight and metabolic condition were monitored. RESULTS: Six mice were used to adapt the surgical technique. Afterwards, another 7 mice were scheduled for OAGB without further complications. The newly established OAGB procedure resulted in significant weight loss and improvement of glucose metabolism 2 weeks after the operation. CONCLUSIONS: The operation presented here is an easy-to-learn and physiologic mouse model of OAGB that can be used for further studies in mice.

Comparison of mini-gastric bypass with sleeve gastrectomy in a mainly super-obese patient group: first results.

INTRODUCTION: Whereas sleeve gastrectomy (SG) in its beginnings was mainly performed to treat super-obesity, it has become as popular as gastric bypass in the treatment of obesity of any class. In contrast to this, the persisting problems of early staple line leaks and poor long-term results of SG regarding weight loss and new onset of gastroesophageal reflux have become increasingly obvious. The mini-gastric bypass (MGB) with its low complication rates and possibly better long-term results may be a good alternative to SG, especially in super-obesity. METHODS: In this context, two groups of mostly super-obese patients (SG and MGB) of a single bariatric center were retrospectively analyzed and compared for perioperative and early postoperative outcomes. RESULTS: Between August 2007 and March 2015, 169 patients underwent MGB, while 118 patients were operated by SG. Both groups were comparable for BMI at baseline (MGB = 54.1 kg/m2 vs. SG = 54.6 kg/m2, p = 0.657). Mean operation time (81.7 vs. 112.1 min, p < 0.0001) as well as hospital stay was lower in the MGB-group (4.5 vs. 7.2 days, p < 0.0001). Perioperative (30 days) mortality was 0 % in MGB versus 0.8 % in SG (one patient). Perioperative complication rate was also lower in the MGB-group (3.0 vs. 9.3 %, p = 0.449). %EWL was significantly better after 1 year in MGB: 66.2 % (±13.9 %) versus 57.3 % (±19.0 %) in SG (p < 0.0001), as well as BMI which was 34.9 kg/m2 (±4.8 kg/m2) in MGB versus 38.5 kg/m2 (±8.6 kg/m2) in SG (p = 0.001). CONCLUSIONS: MGB achieved superior weight loss at 1 year and had a lower 30-day complication rate in comparison with SG for super-obese patients. Thus, MGB might be superior to SG regarding the treatment of super-obesity.