Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective "jejunization" of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.
"Although FXR has been shown to increase adiponectin secretion, its overall effect on proinflammatory adipokines in relation to insulin sensitivity of the adipose tissue has not yet been explored. We hypothesized that, FXR activation by bile acid results in restoration of disturbed adipokine secretion as the mechanism behind the metabolic surgery mediated improvement in insulin resistance for which there have been several confounding evidences (Kohli et al., 2013, 2010; Lefebvre et al., 2009; Thomas et al., 2008; Wei et al., 2009; Ryan et al., 2014). We explored the role of Chenodeoxycholic acid, a well-known endogenous FXR receptor agonist on adipokine secretion, insulin resistance and inflammation using palmitate treated 3T3-L1 cells (Ajuwon and Spurlock, 2005; Reynoso et al., 2003) and High fat diet (HFD) rats (Srinivasan et al., 2005) as in vitro and in vivo model of insulin resistance. "
[Show abstract][Hide abstract] ABSTRACT: Adipose tissue secretes adipokines that regulate insulin sensitivity in adipocytes and other peripheral tissues critical to glucose metabolism. Insulin resistance is associated with severe alterations in adipokines characterized by release of increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines from adipose tissue. The role of Farnesoid X receptor (FXR) activation on adipokines in relation to adipose tissue inflammation and insulin resistance is not completely explored. For the first time, we have evaluated the ability of Chenodeoxycholic acid (CDCA), an endogenous FXR ligand, in restoring the disturbance in adipokine secretion and insulin resistance in palmitate treated 3T3-L1 cells and adipose tissues of High fat diet (HFD) rats. CDCA suppressed several of the tested pro-inflammatory adipokines (TNF-α, MCP-1, IL-6, Chemerin, PAI, RBP4, resistin, vaspin), and enhanced the major anti-inflammatory and insulin sensitizing adipokines (adiponectin, leptin). CDCA suppressed the activation of critical inflammatory regulators such as NF-κB and IKKβ which are activated by palmitate treatment in differentiated cells and HFD in rats. We show the altered adipokines in insulin resistance, its association with inflammatory regulators, and the role of CDCA in amelioration of insulin resistance by modulation of adipokines.
"Several mechanistic explanations have been proposed to explain the improvement in insulin sensitivity following different bariatric surgeries. Clinical studies have uncovered the existence of a substantial positive correlation between elevated bile acid and concomitant increase in functional adiponectin levels after specific type of bariatric surgeries (Kohli et al., 2013; Nakatani et al., 2009; Kohli et al., 2010). Adiponectin is a strong insulin sensitizing, anti-inflammatory adipokine abundantly produced from adipose tissue (Conde et al., 2011). "
"Given that ileum is the major site for bile acid reabsorption, that bile acids play an important role in lipid metabolism, and that circulating bile acids and fibroblast growth factors are often increased following RYGB together with diabetic improvements in humans (Gerhard et al. 2013; Simonen et al. 2012), the mechanisms by which IT alters bile acid metabolism are just being characterized. Circulating concentrations of total, primary, conjugated, and non-conjugated bile acids have been shown to be increased in rats following IT surgery (Cummings et al. 2010, 2013; Kohli et al. 2010; Mencarelli et al. 2013). These changes are associated with an upregulation of the molecules that stimulate bile acid uptake in the intestine (e.g., ASBT, GPBAR1) and a downregulation of transcripts of key molecules involved in bile acid synthesis in the liver (e.g., Cyp7A1, Cyp8B1, Cyp7B1, Cyp27A1) (Cummings et al. 2013; Kohli et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: Bariatric surgeries produce weight loss with improvements in diabetic control through multiple mechanisms, including enhanced stimulation of the lower gut. The ileal transposition surgery was initially developed to gain insights into the lower gut mechanisms that contribute to the anorexic and weight loss effects of roux-en-Y gastric bypass, without the confounds of gastric restriction or foregut exclusion. Though ileal transposition surgery leads to hypophagia and weight loss, depending on the length of the ileum transposed, remarkably, improvements in glycemic control occur independent of changes in body weight. Some of the mechanisms that have been proposed, to explain the weight loss and glycemic benefits of ileal transposition surgery, include enhanced lower gut stimulation and consequent adaptation, increased secretion of lower gut peptides such as glucagon-like peptide-1 and peptide YY, alterations in enterohepatic bile acid metabolism, and improvements in glucose and lipid metabolism in liver, muscle, and adipose tissue. A greater understanding of the mechanisms of action of ileal transposition surgery may lead to the development of more effective and less invasive interventions that can reproduce the effects of the surgery, without attendant surgical risks and long-term complications.
Obesity and Diabetes, 01/2015: pages 143-152; , ISBN: 978-3-319-13125-2
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