Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

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

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.

Life-long Maternal Cafeteria Diet Promotes Tissue-Specific Morphological Changes in Male Offspring Adult Rats.

Here, we evaluated whether the exposure of rats to a cafeteria diet pre- and/or post-weaning, alters histological characteristics in the White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and liver of adult male offspring. Female Wistar rats were divided into Control (CTL; fed on standard rodent chow) and Cafeteria (CAF; fed with the cafeteria diet throughout life, including pregnancy and lactation). After birth, only male offspring (F1) were maintained and received the CTL or CAF diets; originating four experimental groups: CTL-CTLF1; CTL-CAFF1; CAF-CTLF1; CAF-CAFF1. Data of biometrics, metabolic parameters, liver, BAT and WAT histology were assessed and integrated using the Principal Component Analysis (PCA). According to PCA analysis worse metabolic and biometric characteristics in adulthood are associated with the post-weaning CAF diet compared to pre and post weaning CAF diet. Thus, the CTL-CAFF1 group showed obesity, higher deposition of fat in the liver and BAT and high fasting plasma levels of glucose, triglycerides and cholesterol. Interestingly, the association between pre and post-weaning CAF diet attenuated the obesity and improved the plasma levels of glucose and triglycerides compared to CTL-CAFF1 without avoiding the higher lipid accumulation in BAT and in liver, suggesting that the impact of maternal CAF diet is tissue-specific.

Life-long Maternal Cafeteria Diet Promotes Tissue-Specific Morphological Changes in Male Offspring Adult Rats

ABSTRACT Here, we evaluated whether the exposure of rats to a cafeteria diet pre- and/or post-weaning, alters histological characteristics in the White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and liver of adult male offspring. Female Wistar rats were divided into Control (CTL; fed on standard rodent chow) and Cafeteria (CAF; fed with the cafeteria diet throughout life, including pregnancy and lactation). After birth, only male offspring (F1) were maintained and received the CTL or CAF diets; originating four experimental groups: CTL-CTLF1; CTL-CAFF1; CAF-CTLF1; CAF-CAFF1. Data of biometrics, metabolic parameters, liver, BAT and WAT histology were assessed and integrated using the Principal Component Analysis (PCA). According to PCA analysis worse metabolic and biometric characteristics in adulthood are associated with the post-weaning CAF diet compared to pre and post weaning CAF diet. Thus, the CTL-CAFF1 group showed obesity, higher deposition of fat in the liver and BAT and high fasting plasma levels of glucose, triglycerides and cholesterol. Interestingly, the association between pre and post-weaning CAF diet attenuated the obesity and improved the plasma levels of glucose and triglycerides compared to CTL-CAFF1 without avoiding the higher lipid accumulation in BAT and in liver, suggesting that the impact of maternal CAF diet is tissue-specific.

Benefits of L-alanine or L-arginine supplementation against adiposity and glucose intolerance in monosodium glutamate-induced obesity.

PURPOSE: L-alanine (Ala) and L-arginine (Arg) have been reported to regulate pancreatic ß-cell physiology and to prevent body fat accumulation in diet-induced obesity. Here, we assessed growth and adiposity parameters, glucose tolerance, insulin secretion and the expression of insulin and nutrient-regulated proteins in monosodium glutamate (MSG)-obese mice supplemented with either Ala or Arg. METHODS: Male newborn C57Bl/6 mice received a daily subcutaneous injection of MSG or saline solution (CTL group), during the first 6 days of life. From 30 to 90 days of age, MSG and CTL mice received or not 2.55 % Ala (CAla or MArg groups) or 1.51 % Arg-HCl (CArg or MArg groups) in their drinking water. RESULTS: Adult MSG mice displayed higher adiposity associated with lower phosphorylation of the adipogenic enzyme, ACC, in adipose tissue. Glucose intolerance in MSG mice was linked to lower insulin secretion and to lower expression of IRß in adipose tissue, as well as AS160 phosphorylation in skeletal muscle. Perigonadal fat depots were smaller in Ala and Arg mice, while retroperitoneal fat pads were decreased by Ala supplementation only. Both Ala and Arg improved fed-state glycemia as well as IRß and pAS160 content, but only Ala led to improved glucose tolerance and insulin secretion. Adipostatic signals were increased in MAla mice, as indicated by enhanced AMPK phosphorylation and pACC content in fat depots. CONCLUSIONS: Ala supplementation led to more pronounced metabolic improvements compared to Arg, possibly due to suppression of lipogenesis through activation of the AMPK/ACC pathway.