Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics

Sridharan, Gautham; D'Alessandro, Matthew; Bale, Shyam Sundhar; Bhagat, Vicky; Gagnon, Hugo; Asara, John M.; Uygun, Korkut; Yarmush, Martin L.; Saeidi, Nima

doi:10.1142/s233954781750008x

Cited by 4 publications

(3 citation statements)

References 110 publications

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“…While Sridharan et al reported proteomic analysis of a gastric bypass surgery rat model, the present study is, to our knowledge, the first to perform proteomics on several organs derived from the RYGB surgery and sham control mice, at several time points. Due to the large number of data sets and protein kinetics to analyze, we employed a high-dimensional clustering strategy XINA developed by our group, for the identification of RYGB-induced protein changes within the RL, BL, liver, and pancreas.…”

Section: Discussionmentioning

confidence: 91%

Multiorgan Systems Study Reveals Igfbp7 as a Suppressor of Gluconeogenesis after Gastric Bypass Surgery

et al. 2019

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Roux-en-Y gastric bypass (RYGB) surgery reduces weight in obese patients. A marked decrease in blood glucose levels occurs before weight loss; however, key molecules that improve the glycemic profile remain largely unknown. Using a murine RYGB surgery model, we performed multiorgan proteomics and bioinformatics to monitor the proteins and molecular pathways that change in this early glycemic response. Multiplexed proteomic kinetics data analysis revealed that the Roux limb, biliopancreatic limb, liver, and pancreas each exhibited unique temporal and molecular responses to the RYGB surgery. In addition, protein–protein network analysis indicated that the changes to the microbial environment in the intestine may play a crucial role in the beneficial effects of RYGB surgery. Furthermore, insulin-like growth factor binding protein 7 (Igfbp7) was identified as an early induced protein in the Roux limb. Known secretory properties of Igfbp7 prompted us to further investigate its role as a remote organ regulator of glucose metabolism. Igfbp7 overexpression decreased blood glucose levels in diet-induced obese mice and attenuated gluconeogenic gene expression in the liver. Secreted Igfbp7 appeared to mediate these beneficial effects. These results demonstrate that organs responded differentially to RYGB surgery and indicate that Igfbp7 may play an important role in improving blood glucose levels.

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Section: Discussionmentioning

confidence: 91%

Multiorgan Systems Study Reveals Igfbp7 as a Suppressor of Gluconeogenesis after Gastric Bypass Surgery

et al. 2019

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“…In support of this possibility, hepatic Them2 levels were shown to be markedly reduced in rats following a gastric bypass surgery, which ultimately leads to decreased body weight and decreased hepatosteatosis. (35) The observation that THEM2 expression returned to basal levels in livers of NASH patients may reflect an inflammation-induced failure of this compensatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

Auger

Acuña

et al. 2019

Hepatology

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In nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate within the liver because the rates of fatty acid accrual by uptake from plasma and de novo synthesis exceed elimination by mitochondrial oxidation and secretion as very low‐density lipoprotein (VLDL) triglycerides. Thioesterase superfamily member 2 (Them2) is an acyl‐coenzyme A (CoA) thioesterase that catalyzes the hydrolysis of fatty acyl‐CoAs into free fatty acids plus CoASH. Them2 is highly expressed in the liver, as well as other oxidative tissues. Mice globally lacking Them2 are resistant to diet‐induced obesity and hepatic steatosis, and exhibit improved glucose homeostasis. These phenotypes are attributable, at least in part, to roles of Them2 in the suppression of thermogenesis in brown adipose tissue and insulin signaling in skeletal muscle. To elucidate the hepatic function of Them2, we created mice with liver‐specific deletion of Them2 (L‐Them2‐/‐). Although L‐Them2‐/‐ mice were not protected against excess weight gain, hepatic steatosis or glucose intolerance, they exhibited marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These were attributable to reduced rates of VLDL secretion owing to decreased incorporation of plasma‐derived fatty acids into triglycerides. The absence of hepatic steatosis in L‐Them2‐/‐ mice fed chow was explained by compensatory increases in rates of fatty acid oxidation and by decreased de novo lipogenesis in high fat–fed mice. Consistent with a role for Them2 in hepatic VLDL secretion, THEM2 levels were increased in livers of obese patients with NAFLD characterized by simple steatosis. Conclusion: Them2 functions in the liver to direct fatty acids toward triglyceride synthesis for incorporation into VLDL particles. When taken together with its functions in brown adipose and muscle, these findings suggest that Them2 is a target for the management of NAFLD and dyslipidemia.

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“…A modified RYGB procedure, Roux‐en‐Y esophago‐jejunal bypass was used as the surgical model in the experiment. 35 , 36 With the rat placed on a heating pad throughout the operation, anesthesia was induced with Isoflurane and Meloxicam given subcutaneously (5 mg/kg) immediately prior to the procedure. A 4 cm midline upper abdominal incision was made and Enrofloxacin (10 mg/kg) was injected intraperitoneally.…”

Section: Methodsmentioning

confidence: 99%

Physical properties of food or bile redirection do not contribute to the intestinal adaptations after Roux‐en‐Y Gastric Bypass in rats

Pannu

Chukwudi

Wang

et al. 2022

Obesity Science & Practice

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Objective Metabolic and morphological adaptations of the intestine have been suggested to play a role in the various therapeutic benefits of Roux‐en‐Y Gastric Bypass (RYGB) surgery. However, the precise underlying mechanisms remain unclear. In this study, the effects of physical properties of ingested food and redirection of biliopancreatic secretions on intestinal remodeling were investigated in RYGB operated rats. Methods RYGB employing two different Roux Limb (RL) lengths was performed on high fat diet induced obese rats. Post‐operatively, rats were fed either Solid or isocaloric Liquid diets. Metabolic and morphological remodeling of intestine was compared across both diet forms (Solid and Liquid diets) and surgical models (Short RL and Long RL). Results RYGB surgery in rats induced weight loss and improved glucose tolerance which was independent of physical properties of ingested food and biliopancreatic secretions. Intestinal glucose utilization after RYGB was not determined by either food form or biliopancreatic secretions. The GLUT‐1 expression in RL was not influenced by physical properties of food. Furthermore, both physical properties of food and biliopancreatic secretions showed no effects on intestinal morphological adaptations after RYGB. Conclusion Results of this study demonstrate that physical properties of food and bile redirection are not major determinants of intestinal remodeling after RYGB in rats.

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Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics

Cited by 4 publications

References 110 publications

Multiorgan Systems Study Reveals Igfbp7 as a Suppressor of Gluconeogenesis after Gastric Bypass Surgery

Multiorgan Systems Study Reveals Igfbp7 as a Suppressor of Gluconeogenesis after Gastric Bypass Surgery

Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis

Physical properties of food or bile redirection do not contribute to the intestinal adaptations after Roux‐en‐Y Gastric Bypass in rats

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