Andriy Myronovych

FXR is a molecular target for the effects of vertical sleeve gastrectomy

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.

Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner

Our objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG).

A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery

Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, whereas short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short circuiting the normal enterohepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the middistal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis, and endoplasmic reticulum (ER) stress were measured. Rats post-BD lost significantly more weight than the SH rats. BD rats gained less fat mass after surgery. BD rats had improved glucose tolerance, increased higher postprandial glucagon-like peptide-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (C/EBP homologous protein mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/ursodeoxycholic acid [UDCA]) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (C/EBP homologous protein mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.

Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia

Objective Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis. Design ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine. Results DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements. Conclusions Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut.

MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet

Saturated fatty acids activate the c-Jun NH₂-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro; however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here, we have used MLK3-deficient mice to examine the role of MLK3 in a saturated-fat diet model of obesity. MLK3-KO mice fed a high-fat diet enriched in medium-chain saturated fatty acids for 16 wk had decreased body fat compared with wild-type (WT) mice due to increased energy expenditure independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow-derived macrophages in vitro, and obesity induced JNK activation, macrophage infiltration into adipose tissue, and expression of proinflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction.

The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice.

Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid‐X‐receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR‐small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.Objective Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA down-regulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. We tested the role of SHP in fatty liver disease (NAFLD) improvement after VSG. Design and Methods Wild type (WT), SHP liver-transgenic (SHP-Tg) and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level & composition, steatosis and BA metabolism gene expression were evaluated. Results Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight but developed hepatic inflammation and had increased ALT. Conclusions VSG produces weight loss independent of SHP status. SHP ablation creates a pro-inflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.

The Role of Small Heterodimer Partner (SHP) in NAFLD Improvement after Vertical Sleeve Gastrectomy in Mice

Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid‐X‐receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR‐small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.Objective Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA down-regulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. We tested the role of SHP in fatty liver disease (NAFLD) improvement after VSG. Design and Methods Wild type (WT), SHP liver-transgenic (SHP-Tg) and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level & composition, steatosis and BA metabolism gene expression were evaluated. Results Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight but developed hepatic inflammation and had increased ALT. Conclusions VSG produces weight loss independent of SHP status. SHP ablation creates a pro-inflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.

Metabolic comparison of one-anastomosis gastric bypass, single-anastomosis duodenal-switch, Roux-en-Y gastric bypass, and vertical sleeve gastrectomy in rat

BACKGROUND One-anastomosis gastric bypass (OAGB) and single-anastomosis duodenal switch (SADS) have become increasingly popular weight loss strategies. However, data directly comparing the effectiveness of these procedures with Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) are limited. OBJECTIVES To examine the metabolic outcomes of OAGB, SADS, RYGB, and SG in a controlled rodent model. SETTING Academic research laboratory, United States. METHODS Surgeries were performed in diet-induced obese Long-Evans rats, and metabolic outcomes were monitored before and for 15 weeks after surgery. RESULTS All bariatric procedures induced weight loss compared with sham that lasted throughout the course of the study. The highest percent fat loss occurred after OAGB and RYGB. All bariatric procedures had improved glucose dynamics associated with an increase in insulin (notably OAGB and SADS) and/or glucagon-like protein-1 secretion. Circulating cholesterol was reduced in OAGB, SG, and RYGB. OAGB and SG additionally decreased circulating triglycerides. Liver triglycerides were most profoundly reduced after OAGB and RYGB. Circulating iron levels were decreased in all surgical groups, associated with a decreased hematocrit value and increased reticulocyte count. The fecal microbiome communities of OAGB, SADS, and RYGB were significantly altered; however, SG exhibited no change in microbiome diversity or composition. CONCLUSIONS These data support the use of the rat for modeling bariatric surgical procedures and highlight the ability of the OAGB to meet or exceed the metabolic improvements of RYGB. These data point to the likelihood that each surgery accomplishes metabolic improvements through both overlapping and distinct mechanisms and warrants further research.

The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice: SHP and NAFLD Resolution Post-VSG

Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid‐X‐receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR‐small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.Objective Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA down-regulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. We tested the role of SHP in fatty liver disease (NAFLD) improvement after VSG. Design and Methods Wild type (WT), SHP liver-transgenic (SHP-Tg) and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level & composition, steatosis and BA metabolism gene expression were evaluated. Results Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight but developed hepatic inflammation and had increased ALT. Conclusions VSG produces weight loss independent of SHP status. SHP ablation creates a pro-inflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.

Mo2044 Sleeve Gastrectomy in Obese Mice Improves NAFLD Independent of Hepatic Small Heterodimer Partner (SHP, Nrob2) Activation

BACKGROUND: Bariatric surgery is an effective method for achieving sustainable weight loss and health benefit in the morbidly obese population. Although inflammatory bowel disease (IBD) is often associated with malnutrition and weight loss, there has been a temporal increase in the prevalence of obesity among IBD patients. We evaluate the effect of IBD on post-surgical complications and health care utilization among inpatient gastric bypass procedures for obesity. METHODS: The Nationwide Inpatient Sample (NIS) was analyzed for all hospitalizations between 1998 through 2011 with accompanying Roux-en-Y gastric bypass surgery (ICD-9-CM 44.31, 44.38, 44.39) for obesity (ICD-9-CM 278, V778, V853V854, V855.4). IBD hospitalizations were identified using ICD-9-CM 555 and 556 in any diagnosis position. Logistic and linear regression analyses were used to assess the effect of IBD on post-operative complications, inpatient mortality, post-operative length of stay, and total charges. Multivariable models were adjusted for age, sex, payer source, medical comorbidities, and hospital size. RESULTS: Of 933,930 inpatient gastric bypasses for obesity, 967 were performed on IBD patients. Most gastric bypass patients were female (81.5%) with a mean age of 43.0 years. Compared with non-IBD patients, IBD patients were more likely to require conversion from laparoscopic to open surgery (odds ratio [OR] 3.30; 95% confidence interval [CI] 1.55 7.04). IBD patients were also significantly more likely to experience post-surgical complications, including seromas (OR 12.46; 95% CI 1.72 90.39), infections (OR 2.80; 95% CI 1.15 6.83), and gastrointestinal issues (e.g., vomiting, ileus, obstruction) (OR 2.77; 95% CI 1.55 4.98). There were no differences in perforation risk (OR 0.88; 95% CI 0.22 3.54), pulmonary (OR 0.73; 95% CI 0.30 1.77) or cardiovascular complications (OR 1.22; 95% CI 0.39 3.83), or death (0.52% vs. 0.22%; OR 2.04; 95% CI 0.28 14.67). Length of stay, post-operative length of stay, and total charges were similar between non-IBD and IBD hospitalizations. CONCLUSION: IBD is associated with seromas, infections, and gastrointestinal complications after bariatric surgery. Risk of other major complications, death, and hospitalization costs were otherwise similar between IBD and non-IBD patients. The rate of conversion from laparoscopic to open surgery was significantly higher in patients with IBD. Bariatric surgery remains a viable option for treatment of obesity in this special population.