Gut adaptation after gastric bypass in humans reveals metabolically significant shift in fuel metabolism.

OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB. METHODS: This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point. RESULTS: RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB. CONCLUSIONS: These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.

Gastrointestinal Hormone Profiles Associated With Enteral Nutrition Tolerance and Gastric Emptying in Pediatric Critical Illness: A Pilot Study.

BACKGROUND: Enteral nutrition (EN) intolerance and delayed gastric emptying are prevalent in pediatric critical illness and limit EN delivery. Gastrointestinal (GI) hormones may be associated with EN intolerance and delayed gastric emptying in this cohort. METHODS: We determined GI hormone levels, time to achieve 50% of EN goal, and gastric emptying in critically ill children. Total amylin, active ghrelin, total glucagon-like peptide-1 (GLP-1), total gastric inhibitory polypeptide, glucagon, and total peptide-YY (PYY) were measured by multiplex assay and cholecystokinin by ELISA. Lower concentrations of acetaminophen at 1 hour (C1h, µg/mL) using the acetaminophen absorption test defined delayed gastric emptying. Correlation, regression analyses, and a principal component analysis were used to examine the association between GI hormones and time to 50% EN goal and C1h. RESULTS: GI hormones were measured in 14 of 21 patients with gastric emptying testing; median age of 11.2 years (6.74-16.3) and 50% male. Increasing hormone levels from GI hormone profile 1 (GLP-1, glucagon, and amylin) correlated with greater time to reach 50% EN goal (R2 = 0.296, P = 0.04). Decreasing hormone levels from GI hormone profile 2 (PYY and ghrelin) correlated with lower C1h and slower gastric emptying (R2 = 0.342, P = 0.02). CONCLUSION: GI hormone profiles are associated with time to achieve 50% of EN goal and gastric emptying in critically ill children. We have described a feasible model to study the role of GI hormones in this cohort, including the potential clinical applicability of GI hormone measurement in the management of delayed gastric emptying.

Intestine-Specific Overexpression of LDLR Enhances Cholesterol Excretion and Induces Metabolic Changes in Male Mice.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatment options for severe obesity and related comorbidities, including hyperlipidemia, a well-established risk factor of cardiovascular diseases. Elucidating the molecular mechanisms underlying the beneficial effects of RYGB may facilitate development of equally effective, but less invasive, treatments. Recent studies have revealed that RYGB increases low-density lipoprotein receptor (LDLR) expression in the intestine of rodents. Therefore, in this study we first examined the effects of RYGB on intestinal cholesterol metabolism in human patients, and we show that they also exhibit profound changes and increased LDLR expression. We then hypothesized that the upregulation of intestinal LDLR may be sufficient to decrease circulating cholesterol levels. To this end, we generated and studied mice that overexpress human LDLR specifically in the intestine. This perturbation significantly affected intestinal metabolism, augmented fecal cholesterol excretion, and induced a reciprocal suppression of the machinery related to luminal cholesterol absorption and bile acid synthesis. Circulating cholesterol levels were significantly decreased and, remarkably, several other metabolic effects were similar to those observed in RYGB-treated rodents and patients, including improved glucose metabolism. These data highlight the importance of intestinal cholesterol metabolism for the beneficial metabolic effects of RYGB and for the treatment of hyperlipidemia.

Time-Dependent Molecular Responses Differ between Gastric Bypass and Dieting but Are Conserved Across Species.

The effectiveness of Roux-en-Y gastric bypass (RYGB) against obesity and its comorbidities has generated excitement about developing new, less invasive treatments that use the same molecular mechanisms. Although controversial, RYGB-induced improvement of metabolic function may not depend entirely upon weight loss. To elucidate the differences between RYGB and dieting, we studied several individual organ molecular responses and generated an integrative, interorgan view of organismal physiology. We also compared murine and human molecular signatures. We show that, although dieting and RYGB can bring about the same degree of weight loss, post-RYGB physiology is very different. RYGB induces distinct, organ-specific adaptations in a temporal pattern that is characterized by energetically demanding processes, which may be coordinated by HIF1a activation and the systemic repression of growth hormone receptor signaling. Many of these responses are conserved in rodents and humans and may contribute to the remarkable ability of surgery to induce and sustain metabolic improvement.

Nonalcoholic fatty liver disease and gastric bypass surgery regulate serum and hepatic levels of pyruvate kinase isoenzyme M2.

Treatment of nonalcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene and protein expression levels of the M2 isoenzyme of pyruvate kinase (PKM2) in the jejunum. Since PKM2 can be secreted in the circulation, our hypothesis was that the circulating levels of PKM2 increase after RYGB. Our data, however, revealed an unexpected finding and a potential new role of PKM2 for the natural history of metabolic syndrome and NAFLD. Contrary to our initial hypothesis, RYGB-treated patients had decreased PKM2 blood levels compared with a well-matched group of patients with severe obesity before RYGB. Interestingly, PKM2 serum concentration correlated with body mass index before but not after the surgery. This prompted us to evaluate other potential mechanisms and sites of PKM2 regulation by the metabolic syndrome and RYGB. We found that in patients with NAFLD and nonalcoholic steatohepatitis (NASH), the liver had increased PKM2 expression levels, and the enzyme appears to be specifically localized in Kupffer cells. The study of murine models of metabolic syndrome and NASH replicated this pattern of expression, further suggesting a metabolic link between hepatic PKM2 and NAFLD. Therefore, we conclude that PKM2 serum and hepatic levels increase in both metabolic syndrome and NAFLD and decrease after RYGB. Thus, PKM2 may represent a new target for monitoring and treatment of NAFLD.