Obesity-induced cardiac lipid accumulation in adult mice is modulated by G protein-coupled receptor kinase 2 levels

Abstract

BackgroundThe leading cause of death among the obese population is heart failure and stroke prompted by structural and functional changes in the heart. The molecular mechanisms that underlie obesity-related cardiac remodeling are complex, and include hemodynamic and metabolic alterations that ultimately affect the functionality of the myocardium. G protein-coupled receptor kinase 2 (GRK2) is an ubiquitous kinase able to desensitize the active form of several G protein-coupled receptors (GPCR) and is known to play an important role in cardiac GPCR modulation. GRK2 has also been recently identified as a negative modulator of insulin signaling and systemic insulin resistance.MethodsWe investigated the effects elicited by GRK2 downregulation in obesity-related cardiac remodeling. For this aim, we used 9 month-old wild type (WT) and GRK2+/− mice, which display circa 50% lower levels of this kinase, fed with either a standard or a high fat diet (HFD) for 30 weeks. In these mice we studied different parameters related to cardiac growth and lipid accumulation.ResultsWe find that GRK2+/− mice are protected from obesity-promoted cardiac and cardiomyocyte hypertrophy and fibrosis. Moreover, the marked intracellular lipid accumulation caused by a HFD in the heart is not observed in these mice. Interestingly, HFD significantly increases cardiac GRK2 levels in WT but not in GRK2+/− mice, suggesting that the beneficial phenotype observed in hemizygous animals correlates with the maintenance of GRK2 levels below a pathological threshold. Low GRK2 protein levels are able to keep the PKA/CREB pathway active and to prevent HFD-induced downregulation of key fatty acid metabolism modulators such as Peroxisome proliferator-activated receptor gamma co-activators (PGC1), thus preserving the expression of cardioprotective proteins such as mitochondrial fusion markers mitofusin MFN1 and OPA1.ConclusionsOur data further define the cellular processes and molecular mechanisms by which GRK2 down-regulation is cardioprotective during diet-induced obesity, reinforcing the protective effect of maintaining low levels of GRK2 under nutritional stress, and showing a role for this kinase in obesity-induced cardiac remodeling and steatosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0474-6) contains supplementary material, which is available to authorized users.

Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury

“…Fatty acid oxidation is a major source of ATP from cardiac energy metabolism and the alteration of cardiac metabolism can reduce cardiac efficiency (Lopaschuk et al 2010). Cardiac mitochondrial metabolism-related proteins PGC1-α and CPT1 are essential proteins for the regulation of cardiac fatty acid oxidation (Duncan 2011, Lucas et al 2016. Our results showed that PGC1-α and CPT1 levels were decreased in the I/R hearts of obese insulin-resistant rats.…”

Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

“…However, in HFD feeding model, the elevated expression of GRK2 promotes IR via inhibition of tyrosine phosphorylation and activation of IRS1/2 [33, 49]. The upregulated GRK2 also impairs myocardial glucose uptake before cardiac dilation, and the reduced function is evident (Table 1), indicating a metabolic remodeling at early stages of HF [50, 51]. Accordingly, overexpression of GRK2 has been shown to reduce myocardial insulin signaling.…”

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies

“…Considering the role of GRK2 in systemic insulin resistance and obesity [110], authors further investigated whether GRK2 is upregulated in cardiac tissue in adult obese or high fat diet (HFD) fed mice and found significantly increased GRK2 protein levels in both conditions. Recent research demonstrated the role of GRK2 in obesity-related cardiac remodeling and lipid accumulation [111]. Moreover, genetic ablation of GRK2 resulted in reversed glucose tolerance and global insulin sensitivity, prevention of further body weight gain, increased fatty acid metabolism and attenuated lipid accumulation and inflammation in the liver in HFD-induced mouse model of obesity and insulin resistance [112].…”