TY - JOUR
T1 - Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2
AU - Vila-Bedmar, Rocio
AU - Cruces-Sande, Marta
AU - Lucas, Elisa
AU - Willemen, Hanneke L.D.M.
AU - Heijnen, Cobi J.
AU - Kavelaars, Annemieke
AU - Mayor, Federico
AU - Murga, Cristina
N1 - Publisher Copyright:
Copyright 2015 by the American Association for the Advancement of Science.
PY - 2015/7/21
Y1 - 2015/7/21
N2 - Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide - binding protein) - coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet - dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.
AB - Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide - binding protein) - coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet - dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.
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U2 - 10.1126/scisignal.aaa4374
DO - 10.1126/scisignal.aaa4374
M3 - Article
C2 - 26198359
AN - SCOPUS:84937704367
SN - 1945-0877
VL - 8
JO - Science signaling
JF - Science signaling
IS - 386
M1 - ra73
ER -