Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects.

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

A microbial metabolite remodels the gut-liver axis following bariatric surgery.

Bariatric surgery is the most effective treatment for type 2 diabetes and is associated with changes in gut metabolites. Previous work uncovered a gut-restricted TGR5 agonist with anti-diabetic properties-cholic acid-7-sulfate (CA7S)-that is elevated following sleeve gastrectomy (SG). Here, we elucidate a microbiome-dependent pathway by which SG increases CA7S production. We show that a microbial metabolite, lithocholic acid (LCA), is increased in murine portal veins post-SG and by activating the vitamin D receptor, induces hepatic mSult2A1/hSULT2A expression to drive CA7S production. An SG-induced shift in the microbiome increases gut expression of the bile acid transporters Asbt and Ostα, which in turn facilitate selective transport of LCA across the gut epithelium. Cecal microbiota transplant from SG animals is sufficient to recreate the pathway in germ-free (GF) animals. Activation of this gut-liver pathway leads to CA7S synthesis and GLP-1 secretion, causally connecting a microbial metabolite with the improvement of diabetic phenotypes.

Pre-operative Predictors of Weight Loss and Weight Regain Following Roux-en-Y Gastric Bypass Surgery: a Prospective Human Study.

BACKGROUND: There are currently few pre-operative predictors of initial and long-term weight loss following bariatric surgery. OBJECTIVES: We evaluated the role of pre-operative patient characteristics and baseline gut and adipose-derived hormones in predicting maximal total body weight loss (WLmax) and risk of weight regain (WR) after Roux-en-Y gastric bypass (RYGB) surgery. METHODS: One hundred five adult patients undergoing primary RYGB were prospectively recruited. Baseline demographics were recorded and fasting plasma glucose, glycosylated hemoglobin (A1C), insulin, glucagon, leptin, active ghrelin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured on day of surgery. RESULTS: Our cohort had a mean age of 44.4 ± 13.0 years, and initial BMI (body mass index) of 45.1 ± 6.7 kg/m2 with mean post-operative follow-up of 40 months. Eighty patients were female and 26 had type 2 diabetes mellitus (T2D). Average WLmax was 35.3 ± 7.4%. On univariate analysis, higher baseline fasting ghrelin, lower age, lower CRP (C-reactive protein), lower A1C, and negative T2D status were associated with greater WLmax (p < 0.05). Controlling for these variables using stepwise multivariate regression, only higher fasting ghrelin and younger age were associated significantly with greater WLmax (p < 0.05). In subgroup multivariate regression analysis of T2D patients, higher ghrelin and glucagon were significantly associated with greater WLmax. Following stepwise multivariate regression, lower initial BMI and lower glucagon were associated with greater WR (p < 0.05). CONCLUSIONS: Incorporation of baseline biological and hormonal markers may help in developing more accurate predictive models for weight loss following bariatric surgery that help inform patient counseling and decision-making.

KLF10 Deficiency in CD4+ T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver.

CD4+ T cells regulate inflammation and metabolism in obesity. An imbalance of CD4+ T regulatory cells (Tregs) is critical in the development of insulin resistance and diabetes. Although cytokine control of this process is well understood, transcriptional regulation is not. KLF10, a member of the Kruppel-like transcription factor family, is an emerging regulator of immune cell function. We generated CD4+-T-cell-specific KLF10 knockout (TKO) mice and identified a predisposition to obesity, insulin resistance, and fatty liver due to defects of CD4+ Treg mobilization to liver and adipose tissue depots and decreased transforming growth factor ß3 (TGF-ß3) release in vitro and in vivo. Adoptive transfer of wild-type CD4+ Tregs fully rescued obesity, insulin resistance, and fatty liver. Mechanistically, TKO Tregs exhibit reduced mitochondrial respiration and glycolysis, phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR signaling, and consequently impaired chemotactic properties. Collectively, our study identifies CD4+ T cell KLF10 as an essential regulator of obesity and insulin resistance by altering Treg metabolism and mobilization.

Comparison of early type 2 diabetes improvement after gastric bypass and sleeve gastrectomy: medication cessation at discharge predicts 1-year outcomes.

BACKGROUND: Although weight loss-dependent type 2 diabetes (T2D) improvement after sleeve gastrectomy (SG) is well documented, whether SG has a weight-independent impact on T2D is less studied. OBJECTIVES: To evaluate early, weight-independent T2D improvement after SG and Roux-en-Y gastric bypass (RYGB) and its relationship to longer-term T2D outcomes. SETTING: University Hospital, United States. METHODS: We completed a retrospective cohort study of patients with T2D who underwent SG (n = 187) or RYGB (n = 246) from 2010 to 2015. Pre- and postoperative parameters, including demographic characteristics, T2D characteristics, and T2D medication requirements, blood glucose, glycosylated hemoglobin, weight, and body mass index, were reviewed. RESULTS: T2D improved within days after both SG and RYGB, with more patients off T2D medications after SG than RYGB (39% versus 25%, respectively; P < .01) at the time of discharge (2.5 ± .8 versus 2.7 ± 1 d; P = .04). Over the initial postoperative 12 months, T2D medication cessation rates remained relatively stable after SG but continued to improve after RYGB (at 12 mo: 52% versus 68%, respectively; P < .05). T2D medication cessation at discharge predicts 12-month T2D medication cessation (92% [RYGB] and 78% [SG] positive predictive value). In a mixed-effects regression model adjusting for weight loss and severity of diabetes, discharge T2D medication cessation remained a significant predictor of T2D outcomes after both RYGB (odds ratio, 51; 95% confidence interval, 16.1-161; P < .0001) and SG (6.4; 95% confidence interval, 2.8-14.7; P < .0001). CONCLUSIONS: Both SG and RYGB lead to high rates of T2D medication cessation within days of surgery, suggesting both operations activate weight loss-independent anti-T2D pathways. T2D medication cessation at discharge is predictive of 12-month T2D outcomes, particularly in noninsulin requiring patients. By 1 year after the surgery, RYGB leads to more weight loss and higher rates of T2D medication cessation than SG.

Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Attenuate Pro-inflammatory Small Intestinal Cytokine Signatures.

BACKGROUND: Bariatric surgery rapidly induces improvements in type 2 diabetes (T2D) in concert with reduction in systemic markers of inflammation. The impact of bariatric surgery on local intestinal immunity is not known. We hypothesize that sleeve gastrectomy (SG) and gastric bypass (RYGB) surgeries resolve obesity-induced intestinal inflammation, thereby promoting T2D resolution. METHODS: SG and RYGB, or control surgery was performed in SD rats (n = 4-6/group). Key cytokines involved in insulin resistance (TNF-α, IFN-γ), inflammasome activation (IL-1ß, IL-18), inflammation resolution (IL-10, IL-33), and Th17 cell responses (IL-17, IL-23) were measured by qPCR in mucosal scrapings of jejunum at 4 weeks post-surgery. Intestinal cytokine expressions were correlated with weight change, systemic and portal glucose, and insulin levels in response to an enteral glucose load. RESULTS: SG downregulated IL-17 and IL-23 in both proximal and distal jejunum, and IFN-γ was reduced only in distal jejunum (p < 0.05). Jejunal IL-17 and IL-23 expression correlated positively with weight changes after SG (0.93 and 0.98, respectively; p < 0.05). Changes in IFN-γ correlated strongly with insulin levels in portal and systemic circulation (0.99 and 0.95, respectively, p < 0.05). As with SG, IFN-γ, IL-17, and IL-23 were significantly reduced by RYGB. RYGB also reduced TNF-α and IL-18 and increased IL-33 levels (p < 0.05). CONCLUSIONS: RYGB and SG reduce expression of pro-inflammatory cytokines IL-17, IL-23, and IFN-γ in the jejunum. RYGB showed attenuation of additional pro-inflammatory cytokines and enhanced expression of IL-33. Post-surgical changes in intestinal IL-17, IL-23, and IFN-γ correlate strongly with changes in weight and glucose-triggered insulin responses.

Phosphorylation of Beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes.

OBJECTIVE: The inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity. METHODS AND RESULTS: We provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the ß3-adrenergic receptor (ß3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type ß3AR exhibited ß3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of ß3AR was mutated to alanine. CONCLUSION: Taken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the ß3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.

Common pathogens in burn wound and changes in their drug sensitivity.

Infection is an important cause of mortality in patients with burns. Rapid emergence of hospital pathogens and antibiotic-resistant organisms necessitate periodic evaluation of bacterial colonisation patterns and antibiogram sensitivity in burn wards. In this study, which was conducted in a 3 months' period in 2009, 106 samples from the wounds of 59 patients admitted in a burn ward were taken, one in the 1st and one between the 3rd and the 7th days. Pseudomonas aeruginosa, Acinetobacter and Klebsiella were the most common Gram-negative and Staphylococcus aureus was the most common Gram-positive organisms recovered from the patients. This study showed a high rate of resistance to the administered antibiotics. The prevalent Gram-negative organisms in our ward were resistant to ceftazidime and imipenem in nearly 90% and 20% of cases, respectively.