RESUMEN
Roux-en-Y gastric bypass (RYGB) is the most efficient intervention in morbid obesity and promotes metabolic improvements in several peripheral tissues. However, the underlying molecular mechanisms are still poorly understood. To further understand the effects of RYGB on peripheral tissues transcriptomes, we determined transcriptome signatures in pancreatic islets, adipose and liver tissue from diet-induced obese (DIO) rats model following RYGB. Whereas RYGB led to discrete gene expression changes in pancreatic islets, substantial transcriptome changes were observed in metabolic and immune signaling pathways in adipose tissue and the liver, indicating major gene adaptive responses in fat-storing tissues. Compared to RYGB DIO rats, peripheral tissue transcriptome signatures were markedly different in caloric restricted weight matching DIO rats, implying that caloric restriction paradigms do not reflect transcriptomic regulations of RYGB induced weight loss. The present gene expression study may serve as a basis for further investigations into molecular regulatory effects in peripheral tissues following RYGB-induced weight loss.
Asunto(s)
Resistencia a la Insulina/genética , Hígado/metabolismo , Obesidad Mórbida/genética , Obesidad/genética , Transcriptoma/genética , Tejido Adiposo/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Derivación Gástrica , Humanos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Islotes Pancreáticos/cirugía , Hígado/patología , Masculino , Obesidad/etiología , Obesidad/patología , Obesidad/cirugía , Obesidad Mórbida/metabolismo , Obesidad Mórbida/patología , Obesidad Mórbida/cirugía , Ratas , Ratas Sprague-Dawley , Pérdida de Peso/genéticaRESUMEN
OBJECTIVE: Roux-en-Y gastric bypass (RYGB) leads to rapid remission of type 2 diabetes (T2D) and sustained body weight loss, but the underlying molecular mechanisms are still not fully understood. To further elucidate these mechanisms and identify potentially novel preprohormone encoding genes with anti-diabetic and/or anti-obesity properties, we performed a comprehensive analysis of gene expression changes in enteroendocrine cells after RYGB in diet-induced obese (DIO) rats. METHODS: The mRNA expression profiles of enteroendocrine cell enriched samples were characterized at 9, 22 and 60 days after RYGB surgery in a DIO rat model. Enteroendocrine cells were identified by chromogranin A immunohistochemistry and isolated by laser capture microdissection (LCM) from five regions covering the full rostro-caudal extension of the gastrointestinal (GI) tract. RNA sequencing and bioinformatic analyses were subsequently applied to identify differentially expressed preprohormone encoding genes. RESULTS: From the analysis of enteroendocrine cell mRNA expression profiles, a total of 54 preprohormones encoding genes were found to be differentially regulated at one or more time-points following RYGB. These included well-known RYGB associated preprohormone genes (e.g. Gcg, Cck, Gip, Pyy and Sct) and less characterized genes with putative metabolic effects (e.g. Nmu, Guca2a, Guca2b, Npw and Adm), but also 16 predicted novel preprohormone genes. Among the list of gene transcripts, Npw, Apln and Fam3d were further validated using in situ mRNA hybridization and corresponding peptides were characterized for acute effects on food intake and glucose tolerance in mice. CONCLUSION: We present a comprehensive mRNA expression profile of chromogranin A positive enteroendocrine cells following RYGB in rats. The data provides a region-specific characterization of all regulated preprohormone encoding genes in the rat GI tract including 16 not hitherto known. The comprehensive catalogue of preprohormone expression changes may support our understanding of hormone mediated effects of RYGB on diabetes remission and body weight reduction.
