Abstract
Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.
Highlights
Obesity is strongly associated with cardiometabolic risk factors[1], which is reflected by an increased risk for arterial hypertension, heart failure and type 2 diabetes[2]
We recently demonstrated that combined angiotensin type-1 receptor blockers (ARB) and NEP inhibition, using sacubitril/valsartan (LCZ696), improved peripheral insulin sensitivity following 8 weeks of treatment compared to amlodipine (AMLO) in obese hypertensive patients[10]
We demonstrated that sacubitril/valsartan treatment did not significantly alter adipose tissue gene and protein expression of factors related to lipolysis, natriuretic peptide signaling and oxidative metabolism
Summary
Obesity is strongly associated with cardiometabolic risk factors[1], which is reflected by an increased risk for arterial hypertension, heart failure and type 2 diabetes[2]. Combined RAS blockade and NEP inhibition might have synergistic beneficial effects on blood pressure and peripheral insulin sensitivity. We recently demonstrated that combined ARB and NEP inhibition, using sacubitril/valsartan (LCZ696), improved peripheral insulin sensitivity following 8 weeks of treatment compared to amlodipine (AMLO) in obese hypertensive patients[10]. The mechanisms underlying these beneficial effects remain to be established Evidence suggests that both the RAS and ANP affect adipose tissue metabolism, thereby determining insulin sensitivity[6,11]. It is hypothesized that ARB and NEP inhibition with sacubitril/valsartan may affect adipose tissue function, thereby contributing to the observed improved peripheral insulin sensitivity in obese individuals[10]. The present study investigated the effects of sacubitril/valsartan compared to amlodipine treatment for 8 weeks on the abdominal subcutaneous adipose tissue transcriptome and protein expression profiles in obese hypertensive individuals
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