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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.

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.

information on anti-inflammatory or metabolic role of GPR120 at the level of intestinal epithelium is very limited. Further, GPR120 has been shown to be expressed in the intestine, however, its levels along the length of the intestine in various species have not been studied in detail. Aims: Our current studies, therefore, assessed the expression of GPR120 along the length of human, mouse and rat intestine. Further, we examined the anti-inflammatory effects and/or altered levels of the key aneroxigenic gut hormone glucagon-like peptide 1 (GLP1) in (i) model human intestinal epithelial Caco-2 and (ii) model mouse intestinal epithelial endocrine cell line STC-1 following GPR120 activation by synthetic (GW9508) or natural (ω-3 FA) agonists. Results: Both GPR120 mRNA and protein levels varied along the length of mouse and rat intestine in the order of proximal colon>cecum>distal colon>ileum>jejunum. Mucosal scrapings of different regions of organ donor human intestine also showed highest GPR120 protein level in the proximal colon. Cell-surface biotinylation and co-immunoprecipitation in Caco-2 cells, respectively, showed that GPR120 was internalized and bound to β-arrestin-2, a downstream signaling component of NF-κB activation, in response to 30 min exposure to GW9508 (50 μM) or eicosapentaenoic acid (EPA) (100 μM). These treatments also inhibited NF-κB reporter activity presumably via GPR120 binding to and sequestration of β-arrestin-2, inhibiting downstream signaling events. On the other hand, treatment of STC-1 cells with EPA or 10-trans,12-cis conjugated linoleic acid (100 μM, 6 hr) induced GLP1 intensity, as measured by immunofluorescence. However, in STC1 cells, GW9508/EPA treatments did not induce receptor internalization or sequestration of β-arrestin-2. Conclusion: Our studies for the first time demonstrate that agonist-stimulation of GPR120 in different cell types of the intestinal epithelium induces distinct signaling pathways to exert anti-inflammatory effects and modulate enteroendocrine function. Therefore, GPR120 appears to regulate diverse physiological processes at the level of intestinal epithelium to impact inflammatory and/or metabolic disorders. (Supported by NIH-NIDDK/ Bill & Melinda Gates Foundation).