Roux-en-Y Gastric Bypass Rats Research Articles

Severe Anemia in Sprague-Dawley Rats After Roux-en-Y Gastric Bypass Surgery.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most commonly performed bariatric procedures for weight loss in humans. However, this procedure is not risk-free, and patients may experience complications that include small bowel obstruction, gastrointestinal bleeding, chronic diarrhea, ulcers, malnutrition, and anemia. In particular, anemia is a recognized long-term complication and can be severe. Rats have been used as a model to study the effects of gastric bypass surgeries. They can experience similar complications as people, but the development of severe anemia has not previously been reported in rats. We observed 2 cases of severe anemia in female Sprague-Dawley rats after RYGB surgery. These cases prompted us to further investigate the frequency and severity of anemia after RYGB in rats. Blood work and necropsies were performed on 9 additional female Sprague-Dawley rats (5 with RYGB, 4 with sham surgery). In these 9 rats, only one had signs of clinical anemia. These 3 anemic rats displayed moderate to severe pallor of the eyes and ears. Necropsy findings in anemic RYGB rats included pale internal organs and eccentric heart enlargement, which led to a significantly higher heart:body weight ratio in RYGB rats as compared with sham controls. Anemic rats had either a macrocytic normochromic anemia, consistent with vitamin B12 or folate deficiency, or microcytic hypochromic anemia, indicative of iron deficiency. Researchers who perform RYGB surgery in rats should be aware of the potential complication of severe anemia. Plans for the diagnosis and management of this complication and the development of criteria for humane endpoints for severe anemia are recommended as a refinement to these studies.

The Neural Code for Taste in the Nucleus of the Solitary Tract of Rats with Obesity Following Roux-En-Y Gastric Bypass Surgery.

Previous work has shown that taste responses in the nucleus tractus solitarius (NTS; the first central relay for gustation) are blunted in rats with diet-induced obesity (DIO). Here, we studied whether these effects could be reversed by Roux-en-Y gastric bypass (RYGB) surgery, an effective treatment for obesity. Rats were fed a high energy diet (60% kcal fat; HED) both before and after undergoing RYGB. Electrophysiological responses from NTS cells in unrestrained rats were recorded as they licked tastants from a lick spout. Sweet, salty, and umami tastes, as well as their naturalistic counterparts, were presented. Results were compared with those of lean rats from a previous study. As with DIO rats, NTS cells in RYGB rats were more narrowly tuned, showed weaker responses, and less lick coherence than those in lean rats. Both DIO and RYGB rats licked at a slower rate than lean rats and paused more often during a lick bout. However, unlike DIO rats, the proportion of taste cells in RYGB rats was similar to that in lean rats. Our data show that, despite being maintained on a HED after surgery, RYGB can induce a partial recovery of the deficits seen in the NTS of DIO rats.

Shortening the Biliopancreatic Limb Length of One Anastomosis Gastric Bypass Maintains Glucose Homeostasis Improvement with Limited Weight Loss.

One anastomosis gastric bypass (OAGB) is associated with similar metabolic improvements and weight loss as Roux-en-Y gastric bypass (RYGB). However, this bariatric procedure is still controversial as it is suspected to result in undernutrition. Reducing the size of the biliopancreatic limb of OAGB could be essential to maintain positive outcomes while preventing side effects. The objective of this study was to compare and contrast outcomes of OAGB with two different biliopancreatic limb lengths to RYGB and Sham surgery in obese and non-obese rats. Lean and diet-induced obese Wistar rats were operated on RYGB, OAGB with a short (15 cm OAGB-15) or a long (35 cm OAGB-35) biliopancreatic limb or Sham surgery. Body weight and food intake were monitored over 30 weeks, and rats underwent oral glucose and insulin tolerance tests with a pancreatic and gut hormone secretion assay. Macronutrient absorption was determined by fecal analyses. Statistical analyses used non-parametric one-way or two-way ANOVA tests. Compared to Sham rats, RYGB, OAGB-15 and OAGB-35 rats displayed a significant reduced weight. Weight loss was greater after OAGB-35 than after OAGB-15 or Sham surgery because of transient malabsorption. All OAGB- and RYGB-operated rats displayed an improved pancreatic and gut hormone secretion in response to a meal compared to Sham rats, these effects were independent of limb length, rat weight, and maintained overtime. In conclusion, glucose homeostasis was similarly improved in obese and non-obese OAGB-15 and OAGB-35 rats suggesting that shortening the biliopancreatic limb can improve the metabolic parameters without a major influence on weight.

Changes in plasma ghrelin levels following surgical and non-surgical weight-loss in female rats predict alcohol use

The weight-loss surgery Roux-en Y gastric bypass (RYGB) is a relatively effective, long-term treatment option for patients with morbid obesity. However, accumulating clinical evidence suggests that patients receiving RYGB may be at increased risk of developing alcohol use disorder. This observation has been repeatedly supported by preclinical studies showing rodents increase intake of ethanol (EtOH) after RYGB, and has been further confirmed by human studies. A promising alternative to RYGB is sleeve gastrectomy (SG), which has resulted in decreased EtOH consumption in some rodent studies. The exact mechanism underlying the differential alcohol outcomes after RYGB versus SG has yet to be elucidated. However, the gut hormone ghrelin has emerged as a potential candidate from previous preclinical studies specific to RYGB surgeries and due to its action to stimulate food and alcohol intake and cravings. To directly assess changes in plasma ghrelin levels following weigh loss surgeries in the context of alcohol intake, 24 female rats were separated into three surgical groups receiving RYGB, SG, or Sham surgery followed by caloric restriction to produce adiposity matched controls (Sham-AM). Blood was drawn for fasted and fed plasma ghrelin (acyl and des-acyl) assays at multiple time points: while on a normal diet (ND), after 5-week exposure to a high fat diet (HFD), following surgery, and after a series of two-bottle alcohol choice test with increasing concentrations (2%, 4%, 6%, 8%) of EtOH. Consistent with previous observations, RYGB rats drank more EtOH than SG rats across all concentrations. As expected, fasted ghrelin levels were blunted after HFD feeding, compared to normal diet baseline. After RYGB, fasted ghrelin levels returned to higher levels while remained blunted after SG and Sham-AM. Fed acyl ghrelin levels were significantly increased to above “normal” levels after RYGB, but remain low after SG and Sham-AM. Given that post-RYGB acyl ghrelin levels are raised to a fasted state regardless of actual prandial status, we conclude that RYGB may results in a hormonal state reminiscence of a fasted state with the inability of feeding to inhibit ghrelin production, an effect which could potentially contribute to increased EtOH intake following the surgery. In contrast, following SG, ghrelin levels in rats remain consistent with the fed state regardless of prandial status, potentially explaining lower alcohol intake and lower risk of developing AUD.

Early Postoperative Exposure to High-Fat Diet Does Not Increase Long-Term Weight Loss or Fat Avoidance After Roux-en-Y Gastric Bypass in Rats.

BackgroundBariatric surgery alters food preferences in rats and reportedly decreases desire to consume high-fat high-sugar food in humans. The aim of this study was to investigate whether early post-operative exposure to high-fat food could increase body weight loss after Roux-en-Y gastric bypass (RYGB) by triggering fat avoidance.MethodsMale Wistar rats underwent either RYGB (n = 15) or sham-operations (n = 16). Preoperatively a standardized 4-choice cafeteria diet [dietary options: low-fat/low-sugar (LFLS), low-fat/high-sugar (LFHS), high-fat/low-sugar (HFLS), high-fat/high-sugar (HFHS)] was offered. First, each option was available for 4 days, thereafter rats were offered the 4 options simultaneously for 3 days preoperatively. Post-surgery, 8 rats in the RYGB- and 8 in the sham-group were exposed to a high-fat content diet (Oatmeal + 30% lard, OM+L) for 10 days, while 7 RYGB rats and 8 sham-rats received OM alone. From the 11th postoperative day, the 4-choice cafeteria diet was reintroduced for 55-days. The intake of all available food items, macronutrients and body weight changes were monitored over 8 weeks. Main outcomes were long-term body-weight and daily change in relative caloric intake during the postoperative cafeteria period compared to the preoperative cafeteria.ResultsDuring the first 12 days of postoperative cafeteria access, RYGB-rats exposed to OM+L had a higher mean caloric intake per day than RYGB rats exposed to OM alone (Δ10 kCal, Padj = 0.004), but this difference between the RYGB groups disappeared thereafter. Consequently, in the last 33 days of the postoperative cafeteria diet, the mean body weight of the RYGB+OM+L group was higher compared to RYGB+OM (Δ51 g, Padj < 0.001). RYGB rats, independently from the nutritional intervention, presented a progressive decrease in daily consumption of calories from fat and increased their daily energy intake mainly from non-sugar carbohydrates. No such differences were detected in sham-operated controls exposed to low- or high fat postoperative interventions.ConclusionA progressive decrease in daily fat intake over time was observed after RYGB, independently from the nutritional intervention. This finding confirms that macronutrient preferences undergo progressive changes over time after RYGB and supports the role of ingestive adaptation and learning. Early postoperative exposure to high-fat food failed to accentuate fat avoidance and did not lead to superior weight loss in the long-term.

The Influence of Roux-en-Y Gastric Bypass and Diet on NaCl and Sucrose Taste Detection Thresholds and Number of Circumvallate and Fungiform Taste Buds in Female Rats.

Roux-en-Y gastric bypass (RYGB) in rats attenuates preference for, and intake of, sugar solutions. Additionally, maintenance on a high-fat diet (HFD) reportedly alters behavioral responsiveness to sucrose in rodents in short-term drinking tests. Due to the fact that the behavioral tests to date rely on the hedonic value of the stimulus to drive responsiveness, we sought to determine whether taste detection thresholds to sucrose and NaCl are affected by these manipulations as measured in an operant two-response signal detection paradigm. Female rats were maintained on HFD or chow for 10 weeks, at which point animals received either RYGB or SHAM surgery followed by a gel-based diet and then powdered chow. Upon recovery, half of the rats that were previously on HFD were switched permanently to chow, and the other rats were maintained on their presurgical diets (n = 5–9/diet condition × surgery group for behavioral testing). The rats were then trained and tested in a gustometer. There was a significant interaction between diet condition and surgery on NaCl threshold that was attributable to a lower value in RYGB vs. SHAM rats in the HFD condition, but this failed to survive a Bonferroni correction. Importantly, there were no effects of diet condition or surgery on sucrose thresholds. Additionally, although recent evidence suggests that maintenance on HFD alters taste bud number in the circumvallate papillae (CV) of mice, in a subset of rats, we did not find that diet significantly influenced taste pores in the anterior tongue or CV of female rats. These results suggest that any changes in sucrose responsiveness in intake/preference or hedonically oriented tests in rats as a function of HFD maintenance or RYGB are not attributable to alterations in taste sensitivity.

The Effects of Roux-en-Y Gastric Bypass on Glucose- vs. Fructose-Associated Conditioned Flavor Preference

In rodents, repeated single-bottle exposures to distinctly flavored isocaloric glucose and fructose solutions, two sugars with different metabolic pathways, eventually lead to a preference for the former. Because Roux-en-Y gastric bypass (RYGB) surgery decreases preference for and intake of sugar solutions in rats, we tested whether RYGB would curtail the conditioning of a preference for a glucose-paired vs. fructose-paired flavor. RYGB (♂ n=11; ♀ n=10) and sham-operated (SHAM; ♂ n=9; ♀ n=10) rats were trained with a single bottle (30 min/day) containing 8% glucose solution flavored with either 0.05% grape or cherry Kool-Aid (Glu/CSG) or 8% fructose solution with the alternative Kool-Aid flavor (Fru/CSF) in an alternating fashion for 8 days. To determine baseline preferences, a 4-day 30-min two-bottle test was used to assess preference for Glu/CSG vs. Fru/CSF before training. After training, 2-day 30-min two-bottle tests assessed preference for the a) Glu/CSG (CSG-flavored 8% glucose solution) vs Fru/CSF (CSF-flavored 8% fructose solution), b) CSG- vs. CSF-flavored mixture of 4% glucose & 4% fructose (isocaloric), c) CSG- vs. CSF-flavored 0.2% saccharin (“sweet”, no calories), and d) CSG- vs. CSF-flavored water. During training, only male SHAM rats demonstrated progressively increased intake of Glu/CSG over Fru/CSF, and female SHAM rats displayed a trend. RYGB eliminated any difference in single-bottle intake of these solutions during training, regardless of sex. Like their male and female SHAM counterparts, male RYGB rats displayed a conditioned preference for the CSG-associated stimulus in Tests 1-3. Although female RYGB rats displayed acquisition of the conditioned flavor preference in Test 1, unlike the other groups, when the differential sugar cue between the two solutions was removed in Tests 2 and 3, female rats did not display a CSG preference. When the sugar and sweetener cues were both removed on Test 4, all groups displayed some generalization decrement. Thus, RYGB does not compromise the ability of rats to learn and express a glucose- vs. fructose-associated conditioned flavor preference when the exact CS used in training is presented in testing. The mechanistic basis for the sex difference in the effect of RYGB on the generalization decrement observed in this type of flavor preference learning warrants further study.

Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations.

Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action.

Oromotor and somatic taste reactivity during sucrose meals reveals internal state and stimulus palatability after gastric bypass in rats.

After Roux-en-Y gastric bypass (RYGB), rats consume less high-energy foods and fluids, though whether this reflects a concomitant change in palatability remains unclear. By measuring behavior during intraorally delivered liquid meals across days (1 water, 8 sucrose sessions), we showed that RYGB rats (RYGB, n = 8/sex) consumed less 1.0 M sucrose than their sham surgery counterparts (SHAM, n = 8 males, n = 11 females) but displayed similarly high levels of ingestive taste reactivity responses at the start of infusions. Relative to water, both groups increased intake of sucrose, and ingestive responses were dominated by tongue protrusions rather than mouth movements. Thus, RYGB animals still found sucrose palatable despite consuming less than the SHAM group. As the intraoral infusion progressed but before meal termination, aversive behavior remained low and both RYGB and SHAM animals showed fewer ingestive responses, predominantly mouth movements as opposed to tongue protrusions. This shift in responsiveness unrelated to surgical manipulation suggests negative alliesthesia, or a decreased palatability, as rats approach satiation. Notably, only in RYGB rats, across sessions, there was a striking emergence of aversive behavior immediately after the sucrose meal. Thus, although lower intake in RYGB rats seems independent of the hedonic taste properties of sucrose, taste reactivity behavior in these animals immediately after termination of a liquid meal appears to be influenced by postoral events and reflects a state of nimiety or excessive consumption. Measurement of taste reactivity behaviors during an intraorally delivered meal represents a promising way to make inferences about internal state in nonverbal preclinical models.

Protective effects of different types of bariatric surgeries on myocardial ischemia-reperfusion injury in non-obese non-diabetic rats

Abstract Introduction Prior bariatric surgery (BS) significantly improves survival after myocardial infarction (MI). We assume that reduction in fatal MI after BSs could be attributed to the infarct size-limiting effect of the interventions and that this effect is not associated with an improvements in the diabetes mellitus and obesity. Purpose The aim of the study was to evaluate the infarct-limiting effect of various types of bariatric surgery in non-obese non-diabetic rats. Methods Rats were randomized into the following groups: no surgery (CON), sham surgery (SHAM), Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and ileal transposition (IT). 10 weeks after BS, the animals were subjected to ischemia-reperfusion, followed by histochemical determination of infarct area (IA) and no-reflow zone. At the 90th minute of reperfusion, all animals were injected intravenously with indocyanine green at a dose of 1 mg/kg to measure size of no-reflow zone. Results None of bariatric surgery procedures led to body weight reduction. A temporal high postprandial glucose was observed during oral glucose tolerance test (OGTT) in SG and RYGB rats at 30th minute followed by decrease at 120 minutes in comparison with SHAM. Blood insulin concentration increased at 60th minutes in response to OGTT glucose in the SG group compared to CON and SHAM. On the contrary, there was a decrease in insulin level in the IT group after 60 and 120 minutes. In RYGB, basal leptin was low at 120 minutes after glucose administration, while in SG it decreased at 60 and 120 minutes compared with CON and SHAM. Compared to the SHAM, the rats with RYGB and SG had lower IA by 22% and 10% and no-reflow size by 38% and 32%. Conclusions We demonstrated that both bariatric surgeries procedures, RYGB and SG, increase myocardial tolerance to ischemia-reperfusion injury in rats without diabetes and obesity. The infarct-limiting effect was accompanied by a significant decrease in basal plasma leptin level. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Care of Russian Federation. Governmental funding research

Weight loss from caloric restriction vs Roux-en-Y gastric bypass surgery differentially regulates systemic and portal vein GDF15 levels in obese Zucker fatty rats

Weight loss from caloric restriction (i.e. dieting) tends to be modest and short-lived, whereas from bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) is pronounced and generally sustained. The reasons behind these opposing outcomes between interventions remain unclear, but likely involve differential effects on gut-brain communication. Growth differentiation factor 15 (GDF15) is a ubiquitously-induced, centrally-acting, anorexigenic cytokine whose systemic levels are elevated under a variety of conditions associated with a negative energy balance, including in patients following RYGB. We therefore asked whether systemic and portal vein GDF15 levels differ between obese Zucker fatty rats that experienced similar weight loss from RYGB or from forced caloric restriction (CR). Compared with ad libitum fed (ALF) controls, body weight, visceral adiposity and food intake of RYGB and CR rats were markedly lower during the postoperative observation period. Both systemic and portal vein GDF15 levels in RYGB rats at postoperative day 28 were higher compared with ALF rats and particularly compared with CR rats. Further, systemic and portal vein GDF15 levels negatively correlated with body weight and food intake specifically in RYGB rats. These findings provide evidence that, unlike dieting, RYGB might achieve sustained weight loss and appetite suppression partly through increased GDF15 release from epithelial cells of the gastrointestinal tract.

Morphological alterations in gastrointestinal organs of western-diet obese rats submitted to vertical sleeve gastrectomy or Roux-en-Y gastric bypass

Abstract To assess the effect of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) on the esophageal and intestinal morphology of western diet (WD)-obese rats and to characterize the stomach histopathology of WD rats submitted to VSG. Male Wistar rats received WD from 2-4 months of age, to induce obesity, before randomly submitting them to pseudo (WD-SHAM), VSG (WD-VSG) or RYGB (WD-RYGB) surgeries. Gastrointestinal histomorphometry was performed at 3-months post-surgery. The upper esophagus of VSG and RYGB rats increased luminal area, while reductions in the keratin layer of the mucosa and the tunica muscularis were observed only in the RYGB animals. In the lower esophagus, both surgeries increased keratin layer thickness, but reduced the mucosal mucus content, while RYGB increased the thickness of the tunica mucosa and muscularis. The glandular region of the stomach of WD-VSG rats exhibited hypotrophy, epithelial erosion, fibrosis and moderate inflammatory infiltration. VSG and RYGB increased the villi height in the ileum, and the thickness of the tunica muscularis in the jejunum and ileum of WD rats; furthermore, RYGB augmented the ileal villi height. Thus both approaches induced histomorphological alterations in the esophagus and intestine and VSG damaged the gastric mucosa, even over the long-term.

Effects of gastric bypass surgery on expression of glucose transporters and fibrotic biomarkers in kidney of diabetic fatty rats.

Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy. To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy. Academic laboratories. Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways. Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P < .001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfβ) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals. Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFβ pathway.

Gastric bypass in female rats lowers concentrated sugar solution intake and preference without affecting brief-access licking after long-term sugar exposure.

In rodents, Roux-en-Y gastric bypass (RYGB) decreases intake of, and preference for, foods or fluids that are high in sugar. Whether these surgically induced changes are due to decreases in the palatability of sugar stimuli is controversial. We used RYGB and sham-operated (SHAM) female rats to test the influence of prolonged ingestive experience with sugar solutions on the motivational potency of these stimuli to drive licking in brief-access (BA) tests. In experiment 1, RYGB attenuated intake of, and caloric preference for, 0.3 M sucrose during five consecutive, 46-h two-bottle tests (TBTs; sucrose). A second series of TBTs (5 consecutive, 46-h tests) with 1.0 M sucrose revealed similar results, except fluid preference for 1.0 M sucrose also significantly decreased. Before, between, and after the two series of TBTs, two sessions of BA tests (30 min; 10-s trials) with an array of sucrose concentrations (0 and 0.01-1.0 M) were conducted. Concentration-dependent licking and overall trial initiation did not differ between surgical groups in any test. In a similar experimental design in a second cohort of female rats, 0.6 and 2.0 M glucose (isocaloric with sucrose concentrations in experiment 1) were used in the TBTs; 0 and 0.06-2.0 M glucose were used in the BA tests. Outcomes were similar to those for experiment 1, except RYGB rats initiated fewer trials during the BA tests. Although RYGB profoundly affected intake of, and caloric preference for, sugar solutions and, with high concentrations, fluid preference, RYGB never influenced the motivational potency of sucrose or glucose to drive concentration-dependent licking in BA tests.

Roux-En-Y Gastric Bypass Surgery Rebalances Glycemic Control by Increasing Glucose Consumption in Nonobese Diabetic Rat Models: Making 'Normal' Functions 'Abnormal'

Background: Metabolic surgery has been increasingly recommended for obese diabetic patients, but questions remain as to its effectiveness for nonobese diabetic patients and its mechanism that leads to glucose homeostasis independently of weight loss. Methods: We evaluated the role of the Roux limb (RL) in Roux-en-Y gastric bypass (RYGB) surgery, which facilitates food outflow from the upper stomach pouch in nonobese diabetic rat models. Findings: Improvements in glucose metabolism were greater in the long-RL RYGB group than in the other operated RYGB groups or the Goto-Kakizaki (GK) controls. Moreover, diabetes remission by RYGB was found to be remarkably different from both the healthy and diabetic states in the analysis of transcriptome profiles of three rat models individually representing different physiological states. Furthermore, according to a functional analysis, RYGB surgery significantly affected one group of genes, i.e., the new-changed group, which was originally normal (not significantly different between GK and Wistar rats) but became abnormal in the RYGB group (significantly different between RYGB and Wistar rats), despite their diabetes remission. We further observed that novel of this new-changed group induced by RYGB played key roles in improved glycemic control to help rebalance intestinal glucose metabolism. In particular, an increase in newly synthesized cholesterol (CHOL) enriched by the new-changed group increased glucose consumption, which contributed to glucose homeostasis, as demonstrated by a biodistribution analysis using [14C]-labeled glucose. Interpretation: Our findings suggest glycometabolic rebalance by RYGB-induced dysfunctions in the new-changed group as a compensatory role contributes to diabetes remission. Additionally, we propose long-RL RYGB for diabetic patients without morbid obesity. Funding: National Key R&D Program of China (No. 2017YFA0505500), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB13040700), National Natural Science Foundation of China (Nos. 81471047, 31771476 and 81802354), and Shanghai Sailing Program (No. 18YF1420700). Author contributions Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: All experiments were in compliance with NIH guidelines and the Guide for the Care and Use of Laboratory Animals and were approved by the Chinese Academy of Science Institutional Animal Care and Use Committee.

Bariatric Surgery in Rats Upregulates FSP27 Expression in Fat Tissue to Affect Fat Hydrolysis and Metabolism.

Purpose To explore the changes in FSP27 expression and fat metabolism in adipose tissue and their relationship after bariatric surgery in rats. Method Food intake, body weight, triglyceride content, fat distribution, and fat cell morphology were evaluated in rats grouped into control, sham, sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) groups. Immunohistochemistry and western blotting were used to detect protein expression and real-time PCR was used to detect mRNA expression. Mouse 3T3-L1 preadipocytes were used to assess the effects of different energy levels and nutrient factors on FSP27 in adipocytes. Result Food intake, body weight, and triglyceride levels were reduced in RYGB and SG rats within 28 days after surgery, with a more pronounced effect in the RYGB group. Weight loss was mainly due to loss of fat mass rather than loss of lean mass, with the most pronounced decrease in trunk fat. FSP27 expression increased in lean rat adipocytes accompanied by increased lipid droplets (LDs). In SG and RYGB rats, the FSP27 protein concentration gradually increased in white adipose tissue (WAT) after operation. Hormone-sensitive lipase (HSL), p-HSL/HSL, Adipose Triglyceride Lipase (ATGL), and Comparative Gene Identification-58 (CGI-58) gradually decreased in SG and RYGB rats, but they were always higher than in control and sham animals. FSP27 was also decreased in 3T3-L1 adipocytes of animals with a high-energy diet. Conclusion FSP27 is associated with rat lipid metabolism and its expression varies with energy and nutrient supply. It can inhibit excessive hydrolysis and fat accumulation by regulating HSL and ATGL expression and by mediating LDs formation.

The appropriate remodeling of extracellular matrix is the key molecular signature in subcutaneous adipose tissue following Roux-en-Y gastric bypass

AimsWe sought to reveal the key molecular signature in subcutaneous adipose tissue (scAT) following Roux-en-Y gastric bypass (RYGB), through bioinformatics analysis and further verification in vivo. Main methodsWe obtained a transcriptome data of scAT from RYGB and sham-operated rats from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were screened and the DEGs-related Gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed. Also, the protein-protein interaction (PPI) network was constructed among the DEGs. Furthermore, we established an experimental rat model to verify the bioinformatics findings. Key findingsUsing the method of bioinformatics, a total of 602 genes were found to be differentially expressed in scAT between the RYGB group and the sham-operated group. GO analysis showed that DEGs were significantly enriched in extracellular matrix(ECM) -associated functions or processes. KEGG pathway analysis revealed that the protein digestion and absorption pathway and ECM-receptor interaction pathway were the most significantly enriched pathways. The genes encoding ECM components and ECM remodeling-related proteins interact substantially in the PPI network. Then the results of rat experimental verified that the gene expression levels of ECM components(Collagen I and III) and ECM cross-linking related proteins(lysyl oxidase and lysyl oxidase-like 1) decreased and ECM dagradation-related proteins increased in scAT following RYGB. These beneficial results were positively associated with improved insulin resistance (IR). SignificanceAppropriate ECM remodeling, primarily the reduction of ECM deposition and cross-linking and the increase of ECM dagradation, may be the key molecular signature in scAT following RYGB.

Gut-brain crosstalk regulates craving for fatty food.

Patients undergoing Roux-en-Y gastric bypass (RYGB) surgery elicit striking loss of body weight. Anatomical re-structuring of the gastrointestinal (GI) tract, leading to reduced caloric intake and changes in food preference, are thought to be the primary drivers of weight loss in bariatric surgery patients. However, the mechanisms by which RYGB surgery causes a reduced preference for fatty foods remain elusive. In a recent report, Hankir et al described how RYGB surgery modulated lipid nutrient signals in the intestine of rats to blunt their craving for fatty food. The authors reported that RYGB surgery restored an endogenous fat-satiety signaling pathway, mediated via oleoylethanolamide (OEA), that was greatly blunted in obese animals. In RYGB rats, high fat diet (HFD) led to increased production of OEA that activated the intestinal peroxisome proliferation activator receptors-α (PPARα). In RYGB rats, activation of PPARα by OEA was accompanied by enhanced dopamine neurotransmission in the dorsal striatum and reduced preference for HFD. The authors showed that OEA-mediated signals to the midbrain were transmitted via the vagus nerve. Interfering with either the production of OEA in enterocytes, or blocking of vagal and striatal D1 receptors signals eliminated the decreased craving for fat in RYGB rats. These studies demonstrated that bariatric surgery led to alterations in the reward circuitry of the brain in RYGB rats and reduced their preference for HFD.

Roux-en-Y gastric bypass surgery suppresses hypothalamic PTP1B protein level and alleviates leptin resistance in obese rats.

The present study aimed to explore the effect of Roux-en-Y gastric bypass (RYGB) surgery on protein tyrosine phosphatase 1B (PTP1B) expression levels and leptin activity in hypothalami of obese rats. Obese rats induced by a high-fat diet (HFD) that underwent RYGB (n=11) or sham operation (SO, n=9), as well as an obese control cohort (Obese, n=10) and an additional normal-diet group (ND, n=10) were used. Food efficiency was measured at 8 weeks post-operation. Plasma leptin levels were evaluated and hypothalamic protein tyrosine phosphatase 1B (PTP1B) levels and leptin signaling activity were examined at the genetic and protein levels. The results indicated that food efficiency was typically lower in RYGB rats compared with that in the Obese and SO rats. In the RYGB group, leptin receptor expression and proopiomelanocortin was significantly higher, while Neuropeptide Y levels were lower than those in the Obese and SO groups. Furthermore, the gene and protein expression levels of PTP1B in the RYGB group were lower, while levels of phosphorylated signal transducer and activator of transcription 3 protein were much higher compared with those in the Obese and SO groups. In conclusion, RYGB surgery significantly suppressed hypothalamic PTP1B protein expression. PTP1B regulation may partially alleviate leptin resistance.

Impact of Roux-en-Y gastric bypass surgery on appetite, alcohol intake behaviors, and midbrain ghrelin signaling in the rat.

Roux-en-Y gastric bypass (RYGB) surgery reduces appetite and stimulates new onset alcohol misuse; however, the genesis of these behavioral changes is unclear. This study is hypothesized that new onset alcohol intake is a behavioral adaptation that occurs secondary to reduced appetite and correlates with altered central ghrelin signaling. Hedonic high-fat diet (HFD) intake was evaluated prior to the assessment of alcohol intake behaviors in RYGB and control rats. Measurements were also taken of circulating ghrelin and ghrelin receptor (GHSR) regulation of neuronal firing in ventral tegmental area (VTA) dopamine (DA) neurons. RYGB rats displayed reduced HFD intake relative to controls. Sham and RYGB rats consumed more alcohol and preferred lower concentrations of alcohol, whereas only RYGB rats escalated alcohol intake during acute withdrawal. Remarkably, GHSR activity, independent of peripheral ghrelin release, set the tonic firing of VTA DA neurons, a response selectively diminished in RYGB rats. This study indicates that gut manipulations lead to increased alcohol intake, whereas RYGB promotes behaviors that may maintain alcohol misuse. Reductions in hedonic feeding and diminished GHSR control of VTA firing further distinguish gut manipulation from complete bypass and present a potential mechanism linking reduced appetite with alcohol misuse after RYGB surgery.