RESUMEN
The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)(mRID1) in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRT(mRID1) mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRT(mRID1) mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT(mRID1) mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases.
Asunto(s)
Tejido Adiposo/metabolismo , Dieta/efectos adversos , Resistencia a la Insulina , Co-Represor 2 de Receptor Nuclear/fisiología , Obesidad/etiología , Fosforilación Oxidativa , Animales , Homeostasis , Metabolismo de los Lípidos , Hígado/metabolismo , RatonesRESUMEN
The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRT(mRID)) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT(mRID) mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRT(mRID) mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT(mRID)-derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.
Asunto(s)
Adipogénesis/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Represoras/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/genética , Animales , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Genes Letales , Glucosa/metabolismo , Homeostasis/genética , Ratones , Ratones Mutantes , Co-Represor 2 de Receptor Nuclear , PPAR gamma/metabolismo , Estructura Terciaria de Proteína , Proteínas Represoras/genética , Hormonas Tiroideas/metabolismoRESUMEN
The transcriptional corepressor SMRT utilizes two major receptor-interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRT(mRID1)) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRT(mRID1) cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.
Asunto(s)
Envejecimiento/metabolismo , Epigénesis Genética/fisiología , Co-Represor 2 de Receptor Nuclear/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/fisiología , Adiponectina/genética , Adiponectina/metabolismo , Factores de Edad , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Perfilación de la Expresión Génica , Humanos , Ratones , Mitocondrias/metabolismo , Co-Represor 2 de Receptor Nuclear/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1beta protein [PGC-1beta knockout (KO) mice]. PGC-1beta KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions. However, the KO mice displayed an altered expression in a large number of nuclear-encoded genes governing mitochondrial and metabolic functions in multiple tissues including heart, skeletal muscle, brain, brown adipose tissue, and liver. In contrast to PGC-1alpha KO mice that are reportedly hyperactive, PGC-1beta KO mice show greatly decreased activity during the dark cycle. When acutely exposed to cold, the KO mice developed abnormal hypothermia and morbidity. Furthermore, high-fat feeding induced hepatic steatosis and increased serum triglyceride and cholesterol levels in the KO mice. These results suggest that PGC-1beta in mouse plays a nonredundant role in controlling mitochondrial oxidative energy metabolism.