Effect of Early Life Stress on Obesity-Induced Hypertension in Mice

Grants and Contracts Details

Description

Obesity promotes hypertension (HT), a major risk factor for cardiovascular disease. Epidemiological studies established early life stress (ELS) as a modifiable risk factor for increased body mass index and blood pressure (BP), however the mechanisms mediating this greater susceptibility remain unclear. Experimental studies have demonstrated that adipose tissue is connected to the central nervous in positive feedback between adipose tissue-afferent and efferent-SNS signals known as the adipose afferent reflex (AAR). Specifically, the acute stimulation of afferent nerve fibers (e.g. capsaicin, leptin) elevates BP, renal nerve activity and plasma catecholamines in diet-induced obesity models. Adipose tissue also expresses components of the renin-angiotensin system, which has been constituted as a significant source of angiotensin II (AngII) during obesity. Notably, it has been shown that adipose tissue-specific abrogation of the sole precursor for AngII generation, angiotensinogen (AGT), effectively prevents HFD-induced increases in BP. We will use an advantageous mouse model of ELS that combines postnatal maternal separation and early weaning (MSEW) with high fat diet (HFD)-induced obesity. Our preliminary findings provide considerable support for the novel central hypothesis that postnatal MSEW aggravates obesity-induced HT in adult life by increasing adipose tissue-derived afferent sympatho-excitatory signals and AGT secretion. We will challenge our hypothesis in two specific aims: (1) To test the hypothesis that MSEW aggravates obesity-induced HT via sympatho-excitatory signals derived from the adipose tissue. We will assess the effects of MSEW on the different functional components of AAR in acute and chronic experiments using a novel state of the art technique to determine the adipose tissue-brain axis effects on BP; and (2) To test the hypothesis that MSEW promotes obesity-induced HT by increasing AGT secretion in adipose tissue. We will generate a transgenic mouse with an inducible AGT deletion in adipose tissue and expose them to MSEW and HFD. We will induce the AGT deletion at three time points from postnatal life to adulthood to assess its effects on programing, prevention and reversion of HT. In addition, we will test the role of stress hormones on the AGT gene expression. The outcomes of these studies may provide novel ELS-programmed adipose tissue markers with impact on BP control.
StatusActive
Effective start/end date12/1/1711/30/23

Funding

  • National Heart Lung and Blood Institute: $2,140,056.00

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