Pilot Project for Analia Loria: Role of Adipose Tissue on Early Life Stress-Promoted Obesity Hypertension

Hypertension (HT), a major risk factor for cardiovascular disease (CVD), affects >70 million Americans with annual costs burden nearly $50B. Epidemiological studies unveiled early life stress (ELS) as an independent risk factor for increased blood pressure and body mass index (BMI), although the causative mechanisms remain unclear. We established that repeated postnatal Maternal Separation (MatSep) and early weaning, a mouse paradigm of ELS, worsens obesity and promotes high blood pressure in adult male and female mice fed a high fat diet (HFD). The preliminary studies supporting this application indicate that MatSep induces the activation of the renin-angiotensin system (RAS). Specifically, mice exposed to MatSep display increased adipose tissue-derived angiotensinogen (AGT) secretion, the only known precursor in the angiotensin II (AngII) generation. Furthermore, the literature solidly supports that circulating AngII induces high blood pressure via increasing its de novo synthesis in hypothalamic nuclei implicated in the activation of the sympathetic nervous system. While the development of HT involves the activation of the RAS at multiple levels, we propose that MatSep primes the adipose tissue to produce AGT, serving as the major source of AngII in this model. We will challenge this hypothesis in the following Specific Aim: To test the hypothesis that MatSep exacerbates HT by increasing adipose tissue-derived AGT. We will generate an inducible transgenic mouse to abrogate the adipose tissue-specific AGT gene expression at different time points: at birth (generation of HT), 2 week on HFD (progression of HT), and 10 weeks on HFD (reversion of HT) in MatSep and control mice. In these 3 conditions, we will use the combination of genetic, pharmacological and molecular biology targeting adipose tissue AGT as an approach to decipher link between ELS and CVD.