Exploration of Cardiometabolic and Developmental Significance of Angiotensinogen Expression by Cells Expressing the Leptin Receptor or Agouti-related Peptide

Angiotensin II (ANG II) receptor (AT) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor () and agouti-related peptide (). expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (, encoding AGT) with mice expressing Cre-recombinase via the or promoters to cause cell-specific deletions of ( and mice, respectively). mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body deficiency or disruption in albumin ()-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult mice exhibited normal circulating AGT protein and hepatic mRNA expression but reduced mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that and are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both -Cre and -Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of is critically required for normal renal development and survival.