RESUMEN
OBJECTIVE: Adipose depot mass is tightly regulated to maintain energy homeostasis. AKT is a critical kinase in the insulin-signaling cascade that is required for the process of adipogenesis in vitro. However, the role of AKT in the maintenance and/or function of mature adipocytes in vivo had not been examined. METHODS: To study this, we deleted Akt1 and Akt2 in adipocytes of mice using the AdipoQ-Cre driver. RESULTS: Strikingly, mice lacking adipocyte AKT were severely lipodystrophic, having dramatically reduced gonadal adipose and no discernible subcutaneous or brown adipose tissue. As a result, these mice developed severe insulin resistance accompanied by fatty liver, hepatomegaly and with enlarged islets of Langerhans. CONCLUSIONS: These data reveal the critical role of adipocyte AKT and insulin signaling for maintaining adipose tissue mass.
RESUMEN
During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed "selective insulin resistance" to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states. Moreover, cell-nonautonomous suppression of HGP by insulin depends on a reduction of adipocyte lipolysis and serum FFAs but is independent of vagal efferents or glucagon signaling. These data are consistent with a model in which, during T2DM, intact liver insulin signaling drives enhanced lipogenesis while excess circulating FFAs become a dominant inducer of nonsuppressible HGP.
Asunto(s)
Glucosa/biosíntesis , Hepatocitos/metabolismo , Insulina/metabolismo , Lipogénesis , Transducción de Señal , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Dieta , Vías Eferentes/efectos de los fármacos , Vías Eferentes/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Proteína Forkhead Box O1/metabolismo , Eliminación de Gen , Regulación de la Expresión Génica/efectos de los fármacos , Glucagón/metabolismo , Glucoquinasa/metabolismo , Gluconeogénesis/efectos de los fármacos , Gluconeogénesis/genética , Prueba de Tolerancia a la Glucosa , Heparina/farmacología , Hepatocitos/efectos de los fármacos , Insulina/farmacología , Resistencia a la Insulina , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Hígado/efectos de los fármacos , Hígado/inervación , Hígado/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones Noqueados , Complejos Multiproteicos/metabolismo , Periodo Posprandial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiologíaRESUMEN
Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression.
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Albúminas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Insulina/metabolismo , Animales , Glucemia/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Núcleo Celular/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Proteína Forkhead Box O1 , Hepatocitos/metabolismo , Hígado/metabolismo , Masculino , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , EstreptozocinaRESUMEN
Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin, despite lack of autonomous liver insulin signalling. These data indicate that in the absence of Foxo1, insulin signals via an intermediary extrahepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR-Akt-Foxo1 axis exists to regulate glucose production.
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Glucosa/metabolismo , Hígado/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal/fisiología , Animales , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/fisiología , Gluconeogénesis/fisiología , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Masculino , Ratones , Ratones Noqueados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Insulina/genéticaRESUMEN
Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.
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Factores de Transcripción Forkhead/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Células Cultivadas , Ingestión de Alimentos , Ayuno/metabolismo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Intolerancia a la Glucosa/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Insulina/genética , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Akt is encoded by a gene family for which each isoform serves distinct but overlapping functions. Based on the phenotypes of the germ line gene disruptions, Akt1 has been associated with control of growth, whereas Akt2 has been linked to metabolic regulation. Here we show that Akt1 serves an unexpected role in the regulation of energy metabolism, as mice deficient for Akt1 exhibit protection from diet-induced obesity and its associated insulin resistance. Although skeletal muscle contributes most of the resting and exercising energy expenditure, muscle-specific deletion of Akt1 does not recapitulate the phenotype, indicating that the role of Akt1 in skeletal muscle is cell nonautonomous. These data indicate a previously unknown function of Akt1 in energy metabolism and provide a novel target for treatment of obesity.