RESUMO
The extreme polymorphisms of HLA class I proteins result in structural variations in their peptide binding sites to achieve diversity in Ag presentation. External factors could independently constrict or alter HLA class I peptide repertoires. Such effects of the assembly factor tapasin were assessed for HLA-B*44:05 (Y116) and a close variant, HLA-B*44:02 (D116), which have low and high tapasin dependence, respectively, for their cell surface expression. Analyses of the HLA-B*44:05 peptidomes in the presence and absence of tapasin reveal that peptides with C-terminal tryptophans and higher predicted affinities are preferentially selected by tapasin, coincident with reduced frequencies of peptides with other C-terminal amino acids, including leucine. Comparisons of the HLA-B*44:05 and HLA-B*44:02 peptidomes indicate the expected structure-based alterations near the peptide C termini, but also C-terminal amino acid frequency and predicted affinity changes among the unique and shared peptide groups for B*44:02 and B*44:05. Overall, these findings indicate that the presence of tapasin and the tapasin dependence of assembly alter HLA class I peptide-binding preferences at the peptide C terminus. The particular C-terminal amino acid preferences that are altered by tapasin are expected to be determined by the intrinsic peptide-binding specificities of HLA class I allotypes. Additionally, the findings suggest that tapasin deficiency and reduced tapasin dependence expand the permissive affinities of HLA class I-bound peptides, consistent with prior findings that HLA class I allotypes with low tapasin dependence have increased breadth of CD8+ T cell epitope presentation and are more protective in HIV infections.
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Infecções por HIV , Triptofano , Humanos , Antígeno HLA-B44/metabolismo , Triptofano/metabolismo , Peptídeos/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulinas/metabolismo , Ligação Proteica , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismoRESUMO
Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.
Assuntos
Antígenos de Histocompatibilidade Classe I , Neoplasias , Humanos , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos HLA , Neoplasias/genética , Linfócitos T , Antígenos de Histocompatibilidade Classe II/genética , Mutação/genéticaRESUMO
Activation of CD8 + T cells against pathogens and cancers involves the recognition of antigenic peptides bound to human leukocyte antigen (HLA) class-I proteins. Peptide binding to HLA class I proteins is coordinated by a multi-protein complex called the peptide loading complex (PLC). Tapasin, a key PLC component, facilitates the binding and optimization of HLA class I peptides. However, different HLA class I allotypes have variable requirements for tapasin for their assembly and surface expression. HLA-B*44:02 and HLA-B*44:05, which differ only at residue 116 of their heavy chain sequences, fall at opposite ends of the tapasin-dependency spectrum. HLA-B*44:02 (D116) is highly tapasin-dependent, whereas HLA-B*44:05 (Y116) is highly tapasinindependent. Mass spectrometric comparisons of HLA-B*4405 and HLA-B*44:02 peptidomes were undertaken to better understand the influences of tapasin upon HLA-B44 peptidome compositions. Analyses of the HLA-B*44:05 peptidomes in the presence and absence of tapasin reveal that peptides with the C-terminal tryptophan residues and those with higher predicted binding affinities are selected in the presence of tapasin. Additionally, when tapasin is present, C-terminal tryptophans are also more highly represented among peptides unique to B*44:02 and those shared between B*44:02 and B*44:05, compared with peptides unique to B*44:05. Overall, our findings demonstrate that tapasin influences the C-terminal composition of HLA class I-bound peptides and favors the binding of higher affinity peptides. For the HLA-B44 family, the presence of tapasin or high tapasin-dependence of an allotype results in better binding of peptides with C-terminal tryptophans, consistent with a role for tapasin in stabilizing an open conformation to accommodate bulky C-terminal residues.
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Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.
Assuntos
Cirurgia Bariátrica , Fenômenos Bioquímicos/fisiologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Obesidade Mórbida/cirurgia , Animais , Cirurgia Bariátrica/métodos , Desvio Biliopancreático/métodos , Gastrectomia/métodos , Derivação Gástrica/métodos , Humanos , Camundongos , Obesidade/cirurgia , Obesidade Mórbida/metabolismoRESUMO
OBJECTIVE: Understanding the mechanisms underlying the remarkable beneficial effects of gastric bypass surgery is important for the development of non-surgical therapies or less invasive surgeries in the fight against obesity and metabolic disease. Although the intestinal L-cell hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) have attracted the most attention, direct tests in humans and rodents with pharmacological blockade or genetic deletion of either the GLP1-receptor (GLP1R) or the Y2-receptor (Y2R) were unable to confirm their critical roles in the beneficial effects gastric bypass surgery on body weight and glucose homeostasis. However, new awareness of the power of combinatorial therapies in the treatment of metabolic disease would suggest that combined blockade of more than one signaling pathway may be necessary to reverse the beneficial effects of bariatric surgery. METHODS: The metabolic effects of high-fat diet and the ability of Roux-en-Y gastric bypass surgery to lower food intake and body weight, as well as improve glucose handling, was tested in GLP1R and Y2R-double knockout (GLP1RKO/Y2RKO) and C57BL6J wildtype (WT) mice. RESULTS: GLP1RKO/Y2RKO and WT mice responded similarly for up to 20 weeks on high-fat diet and 16 weeks after RYGB. There were no significant differences in loss of body and liver weight, fat mass, reduced food intake, relative increase in energy expenditure, improved fasting insulin, glucose tolerance, and insulin tolerance between WT and GLP1RKO/Y2RKO mice after RYGB. CONCLUSIONS: Combined loss of GLP1R and Y2R-signaling was not able to negate or attenuate the beneficial effects of RYGB on body weight and glucose homeostasis in mice, suggesting that a larger number of signaling pathways is involved or that the critical pathway has not yet been identified.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Derivação Gástrica , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Cirurgia Bariátrica , Glicemia , Peso Corporal , Metabolismo Energético , Regulação da Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Insulina , Resistência à Insulina , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Peptídeo YY , Receptores Acoplados a Proteínas G/genética , TranscriptomaRESUMO
Gastric bypass surgery is the most effective treatment and is often the only option for subjects with severe obesity. However, investigation of critical molecular mechanisms involved has been hindered by confounding of specific effects of surgery and side effects associated with acute surgical trauma. Here, we dissociate the two components by carrying out surgery in the lean state and testing its effectiveness to prevent diet-induced obesity later in life. Body weight and composition of female mice with RYGB performed at 6 weeks of age were not significantly different from sham-operated and age-matched non-surgical mice at the time of high-fat diet exposure 12 weeks after surgery. These female mice were completely protected from high-fat diet-induced obesity and accompanying metabolic impairments for up to 50 weeks. Similar effects were seen in male mice subjected to RYGB at 5-6 weeks, although growth was slightly inhibited and protection from diet-induced obesity was less complete. The findings confirm that RYGB does not indiscriminately lower body weight but specifically prevents excessive diet-induced obesity and ensuing metabolic impairments. This prevention of obesity model should be crucial for identifying the molecular mechanisms underlying gastric bypass surgery.
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Dieta Hiperlipídica/efeitos adversos , Derivação Gástrica , Obesidade/etiologia , Obesidade/prevenção & controle , Envelhecimento , Animais , Glicemia/análise , Composição Corporal , Peso Corporal , Ingestão de Alimentos , Metabolismo Energético , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismoRESUMO
BACKGROUND/GOALS: The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. METHODS: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet. RESULTS: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. CONCLUSIONS: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Derivação Gástrica , Obesidade/cirurgia , Peptídeo YY/genética , Receptores dos Hormônios Gastrointestinais/genética , Animais , Masculino , Camundongos , Camundongos KnockoutRESUMO
OBJECTIVES: Dieting often fails because weight loss triggers strong counter-regulatory biological responses such as increased hunger and hypometabolism that are thought to be critically dependent on the master fuel sensor in the mediobasal hypothalamus (MBH). Because prolonged starvation has been shown to increase AgRP and NPY, the expression level of these two orexigenic genes has been taken as an experimental readout for the presence or absence of hunger. Roux-en-Y gastric bypass (RYGB) surgery leads to a significant weight loss without inducing the associated hunger, indicating possible changes in hypothalamic neuropeptides and/or signaling. Our goal was to assess key genes in the MBH involved in regulating body weight, appetite, and inflammation/oxidative stress after RYGB surgery in mice. METHODS: Obese mice on a high-fat diet were subjected to either sham or RYGB surgery, or caloric restriction to match the weight of RYGB group. Chow-fed mice without surgery served as an additional control group. After 2 or 12 weeks post-surgery, hypothalamic genes were analyzed by real-time qPCR. RESULTS: During the rapid weight loss phase at 2 weeks after RYGB surgery, hypothalamic AgRP and NPY gene expression was not increased compared to mice with sham surgery, indicating that the mice are not hungry. In contrast, the same weight loss induced by caloric restriction promptly triggered increased AgRP and NPY expression. This differential effect of RYGB and caloric restriction was no longer observed during the weight-maintenance phase at 12 weeks after surgery. A similar differential effect was observed for ObRb, but not for POMC and CART expression. Furthermore, RAGE and IBA-1, two markers for inflammation/oxidative stress, were significantly suppressed after RYGB compared to caloric restriction at 2 weeks post-surgery. CONCLUSIONS: These findings suggest that RYGB prevents the biologically adaptive hunger response triggered by undernutrition and weight loss, and suppresses weight loss-induced hypothalamic inflammation markers.
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Proteína Relacionada com Agouti/análise , Restrição Calórica , Dieta Hiperlipídica , Derivação Gástrica , Hipotálamo/química , Neuropeptídeo Y/análise , Animais , CamundongosRESUMO
BACKGROUND: Nutrient-sensing receptors located on enteroendocrine (EEC) cells modulate appetite via detection of luminal contents. Colonic 'tasting' of luminal contents may influence changes to appetite observed in obesity and after weight loss induced by bariatric surgery. We assessed the effects of obesity and gastric bypass-induced weight loss on expression of nutrient-sensing G-protein coupled receptors (GPCRs), EEC and enterochromaffin (EC) cells and mucosal innervation. METHODS: qPCR and immunohistochemistry were used to study colonic tissue from (a) chow-fed/lean, (b) high-fat fed/obese, (c) Roux-en-Y gastric bypass surgery (RYGB), and (d) calorie restriction-induced weight loss mice. RESULTS: Expression of GPR41, GPR43, GPR40, GPR120, GPR84, GPR119, GPR93 and T1R3 was increased in obese mice. Obesity-induced overexpression of GPR41, 40, 84, and 119 further increased after RYGB whereas GPR120 and T1R3 decreased. RYGB increased TGR5 expression. L-cells, but not EC cells, were increased after RYGB. No differences in mucosal innervation by protein gene product (PGP) 9.5 and GLP-1R-positive nerve fibers were observed. Stimulation of colonic mucosa with GPR41, GPR40, GPR85, GPR119, and TGR5 agonists increased cell activation marker expression. CONCLUSIONS: Several nutrient-sensing receptors induced activation of colonic EEC. Profound adaptive changes to the expression of these receptors occur in response to diet and weight loss induced by RYGB or calorie restriction.
Assuntos
Colo , Sistema Nervoso Entérico/fisiopatologia , Células Enterocromafins/metabolismo , Mucosa Intestinal , Obesidade/cirurgia , Receptores Acoplados a Proteínas G/metabolismo , Redução de Peso/fisiologia , Animais , Restrição Calórica , Células Quimiorreceptoras/metabolismo , Colo/citologia , Colo/inervação , Colo/metabolismo , Dieta Redutora , Derivação Gástrica , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/fisiopatologia , Ubiquitina Tiolesterase/metabolismoRESUMO
BACKGROUND AND PURPOSE: Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective treatments for obesity and type 2 diabetes. Despite this, the mechanisms through which it acts are still not well understood. Bile acid signaling through the transmembrane G-protein-coupled receptor TGR5 has been shown to have significant effects on metabolism and has recently been reported to be necessary for the full effects of vertical sleeve gastrectomy (VSG), a bariatric surgery with similar effects to RYGB. The goal of the current study is therefore to investigate the role of bile acid signaling through TGR5 to see if it is necessary to obtain the full effects of RYGB. METHODS: High-fat diet-induced obese TGR5-/- and wildtype mice (WT) were subjected to RYGB, sham surgery, or weight matching (WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance, insulin sensitivity, and liver weight were measured. RESULTS: Although the difference in fat mass 20 weeks after surgery between RYGB and sham-operated mice was slightly reduced in TGR5-/- mice when compared to wildtype mice, loss of body weight and fat mass from preoperative levels, reduction of food intake, increase of energy expenditure, and improvement in glycemic control were similar in the two genotypes. Furthermore, improvements in glycemic control were similar in non-surgical mice weight-matched to RYGB. CONCLUSIONS: We conclude that bile acid signaling through TGR5 is not required for the beneficial effects of RYGB in the mouse and that RYGB and VSG may achieve their similar beneficial effects through different mechanisms.
Assuntos
Derivação Gástrica/métodos , Obesidade/metabolismo , Obesidade/cirurgia , Receptores Acoplados a Proteínas G/genética , Redução de Peso/fisiologia , Anastomose em-Y de Roux/métodos , Animais , Glicemia/metabolismo , Composição Corporal/genética , Dieta Hiperlipídica , Ingestão de Alimentos , Metabolismo Energético/genética , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Redução de Peso/genéticaRESUMO
BACKGROUND: Weight regain and type-2 diabetes relapse has been reported in a significant proportion of vertical sleeve gastrectomy (VSG) patients in some studies, but definitive conclusions regarding the long-term comparative effectiveness of VSG and Roux-en-Y gastric bypass (RYGB) surgery are lacking both in humans and rodent models. This study's objective was to compare the effects of murine models of VSG and RYGB surgery on body weight, body composition, food intake, energy expenditure, and glycemic control. METHODS: VSG, RYGB, and sham surgery was performed in high-fat diet-induced obese mice, and the effects on body weight and glycemic control were observed for a period of 12 weeks. RESULTS: After the initial weight loss, VSG mice regained significant amounts of body weight and fat mass that were only marginally lower than in sham-operated mice. In contrast, RYGB produced sustained loss of body weight and fat mass up to 12 weeks and drastically improved fasting insulin and HOMA-IR compared with sham-operated mice. Using weight-matched control groups, we also found that the adaptive hypometabolic response to weight loss was blunted by both VSG and RYGB, and that despite large weight/fat regain, fasting insulin and HOMA-IR were markedly improved, but not reversed, in VSG mice. CONCLUSIONS: VSG is less effective to lastingly suppress body weight and improve glycemic control compared with RYGB in mice. Given similar observations in many human studies, the run towards replacing RYGB with VSG is premature and should await carefully controlled randomized long-term trials with VSG and RYGB.
Assuntos
Glicemia/fisiologia , Gastrectomia , Derivação Gástrica , Redução de Peso/fisiologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Gastrectomia/métodos , Gastrectomia/estatística & dados numéricos , Derivação Gástrica/métodos , Derivação Gástrica/estatística & dados numéricos , Camundongos , Camundongos Obesos , Obesidade/cirurgiaRESUMO
OBJECTIVE: The mechanisms by which bariatric surgeries so effectively and lastingly reduce body weight and normalize metabolic dysfunction are not well understood. Fibroblast growth fator-21 (FGF21) is a key regulator of metabolism and is currently considered for treatment of obesity. Although elevated by acute food deprivation, it is downregulated after weight loss induced by chronic calorie restriction but not after Roux-en-Y gastric bypass surgery. Therefore, the goal of the present study was to assess the role of FGF21-signaling in the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB). METHODS: High-fat diet-induced obese FGF21-deficient (FGF21(-/-)) and wildtype (WT) mice were subjected to RYGB, sham surgery, or caloric restriction to match body weight of RYGB mice. Body weight, body composition, food intake, energy expenditure, glucose tolerance, and insulin sensitivity, as well as plasma levels and hepatic mRNA expression of FGF21 were measured. RESULTS: Hepatic expression and plasma levels of FGF21 are higher after RYGB compared with similar weight loss induced by caloric restriction, suggesting that elevated FGF21 might play a role in preventing increased hunger and weight regain after RYGB. However, although the body weight differential between RYGB and sham surgery was significantly reduced in FGF21(-/-) mice, RYGB induced similarly sustained body weight and fat mass loss, initial reduction of food intake, increased energy expenditure, and improvements in glycemic control in FGF21(-/-) and WT mice. CONCLUSIONS: FGF21 signaling is not a critical single factor for the beneficial metabolic effects of RYGB. This may open up the possibility to use FGF21 as adjuvant therapy in patients with ineffective bariatric surgeries.
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OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) results in sustained lowering of body weight in most patients, but the mechanisms involved are poorly understood. The aim of this study was to obtain support for the notion that reprogramming of defended body weight, rather than passive restriction of energy intake, is a fundamental mechanism of RYGB. METHODS: Male C57BL6J mice reaching different degrees of obesity on a high-fat diet either with ad libitum access or with caloric restriction (weight-reduced) were subjected to RYGB. RESULTS: RYGB-induced weight loss and fat mass loss were proportional to pre-surgical levels, with moderately obese mice losing less body weight and fat compared with very obese mice. Remarkably, mice that were weight-reduced to the level of chow controls before surgery immediately gained weight after surgery, exclusively accounted for by lean mass gain. CONCLUSIONS: The results provide additional evidence for reprogramming of a new defended body weight as an important principle by which RYGB lastingly suppresses body weight. RYGB appears to selectively abolish defense of a higher fat mass level, while remaining sensitive to the defense of lean mass. The molecular and physiological mechanisms underlying this reprogramming remain to be elucidated.
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Peso Corporal/fisiologia , Derivação Gástrica , Camundongos Obesos/cirurgia , Obesidade/cirurgia , Aumento de Peso , Animais , Restrição Calórica , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Masculino , CamundongosRESUMO
BACKGROUND: The mechanisms by which Roux-en-Y gastric bypass surgery (RYGB) so effectively lowers body weight and improves glycemic control are not well understood, and murine models are essential for identifying the crucial signaling pathways involved. The aim of this study is to characterize the time course of RYGB on body weight, body composition, food intake, and energy expenditure in diet-induced obese mice and establish a tissue bank for global "omics" or targeted biochemical and structural analyses. METHODS: High-fat diet-induced obese mice were subjected to RYGB using an improved surgical technique with a small gastric pouch. The effects on body weight, body composition, food intake, and energy expenditure were compared to sham surgery, high-fat diet-restricted weight-matched controls, and never-obese chow-fed controls. RESULTS: Without mortality or complications, RYGB surgery in high-fat diet-induced obese mice gradually decreased body weight to a plateau that was more or less sustained for up to 12 weeks (33 g, -18 %, p < 0.01) and significantly lower compared with sham-operated mice (51 g, +25 %, p < 0.01), but higher (+18 %, p < 0.01) than age-matched, chow-fed control mice (27 g). Energy intake after RYGB was significantly suppressed compared to sham only for the first 10 days, but significantly higher compared to weight-matched mice. Energy expenditure after RYGB was higher throughout the study compared with weight-matched, but not sham animals. CONCLUSIONS: RYGB surgery in diet-induced obese mice results in similar body weight and body composition changes as observed in humans, but in contrast with humans, this is achieved mainly through increased energy expenditure rather than decreased food intake.
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Composição Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Derivação Gástrica/métodos , Derivação Gástrica/estatística & dados numéricos , Animais , Peso Corporal , Dieta Hiperlipídica , Modelos Animais de Doenças , Camundongos , Camundongos Obesos , ObesidadeRESUMO
BACKGROUND: Clinical studies have shown similar rapid improvements in body mass and glycemic control after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG). Evidence suggests that adaptive intestinal tissue growth and reprogramming of intestinal glucose disposal play a key role in the beneficial effects on glucose homeostasis after RYGB, but it is not known whether such adaptive changes also occur after sleeve gastrectomy. METHODS: High-fat diet-induced obese rats were subjected to either VSG or RYGB, and intestinal growth and functional adaptations were assessed by using morphometric, immunohistochemical, and immuno-blot techniques, 3 months after surgery or sham surgery. RESULTS: The cross-sectional areas of the Roux and common limbs are significantly increased after RYGB compared with sham surgery (Roux limb: 17.1 ± 4.0 vs. 5.5 ± 0.1 mm(2); common limb: 11.7 ± 0.6 vs. 5.1 ± 0.5 mm(2); p < 0.01), but the cross-sectional area of the corresponding jejunum is not different from controls after VSG. Similarly, mucosal thickness and the number of GLP-1 cells are not increased after VSG. Protein expression of hexokinase II is increased fourfold (p < 0.01) in the Roux limb after RYGB, but not in the jejunum after VSG. CONCLUSIONS: Adaptive hypertrophy and reprogramming of glucose metabolism in the small intestine are not necessary for VSG to improve body composition and glycemic control. The similar beneficial effects of VSG and RYGB on glucose homeostasis might be mediated by different mechanisms.
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Gastrectomia/efeitos adversos , Glucose/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Obesidade Mórbida/cirurgia , Animais , Glicemia/metabolismo , Dieta Hiperlipídica , Metabolismo Energético , Gastrectomia/métodos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipertrofia/etiologia , Jejuno/metabolismo , Jejuno/patologia , Jejuno/cirurgia , Masculino , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: It is conceivable that overstimulation of chemo- and mechano-sensors in the Roux and common limbs by uncontrolled influx of undigested nutrients after Roux-en-Y gastric bypass surgery (RYGB) could lead to exaggerated satiety signaling via vagal afferents and contribute to body weight loss. Because previous clinical and preclinical studies using vagotomy came to different conclusions, the aim was to examine the effects of selective and histologically verified celiac branch vagotomy on reduced food intake and body weight loss induced by RYGB. METHODS: Male Sprague-Dawley rats underwent either RYGB + celiac branch vagotomy (RYGB/VgX, n=15), RYGB + sham celiac branch vagotomy (RYGB/Sham VgX; n=6), Sham RYGB + celiac branch vagotomy (Sham/VgX; n=6), or sham RYGB + sham celiac branch vagotomy (Sham/Sham; n=6), and body weight, body composition, and food choice were monitored for 3 months after intervention. RESULTS: In rats with RYGB, histologically confirmed celiac branch vagotomy significantly moderated weight loss during the first 40 days after surgery, compared to either sham or failed vagotomy (P<0.05). In contrast, celiac branch vagotomy slightly, but non-significantly, reduced body weight gain in sham RYGB rats compared to sham/sham rats. Furthermore, the significant food intake suppression during the first 32 days after RYGB (P<0.05) was also moderated in rats with verified celiac branch vagotomy. CONCLUSIONS: The results suggest that signals carried by vagal afferents from the mid and lower intestines contribute to the early RYGB-induced body weight loss and reduction of food intake.
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Regulação do Apetite/fisiologia , Derivação Gástrica , Obesidade Mórbida/cirurgia , Nervo Vago/fisiologia , Redução de Peso/fisiologia , Animais , Modelos Animais de Doenças , Intestinos/inervação , Masculino , Ratos , Ratos Sprague-Dawley , Vagotomia , Nervo Vago/cirurgiaRESUMO
OBJECTIVE: To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food. METHODS: Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery. RESULTS: SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight. CONCLUSIONS: RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense.
Assuntos
Derivação Gástrica , Hiperfagia , Obesidade/cirurgia , Redução de Peso , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Ingestão de Alimentos , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina/antagonistas & inibidoresRESUMO
Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.