Objective Obesity promotes hypertension, but it is unclear if sex differences exist in obesity-related hypertension. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (AngII) to angiotensin-(1–7) (Ang-[1–7]), controlling peptide balance. We hypothesized that tissue-specific regulation of ACE2 by high-fat (HF) feeding and sex hormones contributes to sex differences in obesity-hypertension. Methods and Results HF-fed females gained more body weight and fat mass than males. HF-fed males exhibiting reduced kidney ACE2 activity had increased plasma angiotensin II levels and decreased plasma Ang-(1–7) levels. In contrast, HF-fed females exhibiting elevated adipose ACE2 activity had increased plasma Ang-(1–7) levels. HF-fed males had elevated systolic and diastolic blood pressure that were abolished by losartan. In contrast, HF-fed females did not exhibit increased systolic blood pressure until females were administered the Ang-(1–7) receptor antagonist, D-Ala-Ang-(1–7). Deficiency of ACE2 increased systolic blood pressure in HF-fed males and females, which was abolished by losartan. Ovariectomy of HF-fed female mice reduced adipose ACE2 activity and plasma Ang-(1–7) levels, and promoted obesity-hypertension. Finally, estrogen, but not other sex hormones, increased adipocyte ACE2 mRNA abundance. Conclusions These results demonstrate that tissue-specific regulation of ACE2 by diet and sex hormones contributes to sex differences in obesity-hypertension.

Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes.Objectives: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor α (TNF-α) and on glucose and insulin homeostasis in lean and obese mice.Methods: We quantified glucose and insulin tolerance, as well as TNF-α levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-α expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis.Results: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77–treated mice, TNF-α expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss.Conclusions: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose-specific elevations in TNF-α expression by PCBs may contribute to impaired glucose homeostasis.

Yiannikouris F, Karounos M, Charnigo R, English VL, Rateri DL, Daugherty A, Cassis LA. Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice. Am J Physiol Regul Integr Comp Physiol 302: R244 -R251, 2012. First published November 9, 2011 doi:10.1152/ajpregu.00323.2011.-Previous studies demonstrated that overexpression of angiotensinogen (AGT) in adipose tissue increased blood pressure. However, the contribution of endogenous AGT in adipocytes to the systemic renin-angiotensin system (RAS) and blood pressure control is undefined. To define a role of adipocytederived AGT, mice with loxP sites flanking exon 2 of the AGT gene (Agt fl/fl ) were bred to transgenic mice expressing Cre recombinase under the control of an adipocyte fatty acid-binding protein 4 promoter (aP2) promoter to generate mice with adipocyte AGT deficiency (Agt aP2 ). AGT mRNA abundance in adipose tissue and AGT secretion from adipocytes were reduced markedly in adipose tissues of Agt aP2 mice. To determine the contribution of adipocyte-derived AGT to the systemic RAS and blood pressure control, mice were fed normal laboratory diet for 2 or 12 mo. In males and females of each genotype, body weight and fat mass increased with age. However, there was no effect of adipocyte AGT deficiency on body weight, fat mass, or adipocyte size. At 2 and 12 mo of age, mice with deficiency of AGT in adipocytes had reduced plasma concentrations of AGT (by 24 -28%) compared with controls. Moreover, mice lacking AGT in adipocytes exhibited reduced systolic blood pressures compared with controls (Agt fl/fl , 117 Ϯ 2; Agt aP2 , 110 Ϯ 2 mmHg; P Ͻ 0.05). These results demonstrate that adipocyte-derived AGT contributes to the systemic RAS and blood pressure control. adipose tissue; age THE RENIN-ANGIOTENSIN SYSTEM (RAS) plays a major role in control of blood pressure. Angiotensinogen (AGT) is the only known precursor for production of angiotensin II (ANG II). ANG II increases blood pressure by increasing peripheral vascular resistance, increasing sympathetic nervous system activity, and through the control of sodium homeostasis. While the systemic RAS is recognized as an important endocrine system for blood pressure control, local production of ANG II by various cell types and/or tissues has also been implicated in the pathophysiology of hypertension.In 1994, Tanimoto et al. (35) demonstrated that mice with whole body deficiency of AGT had marked decreases of systemic concentrations of AGT and blood pressure (by 34 mmHg). These results demonstrated a primary role for AGT in the systemic RAS and blood pressure control. It is generally accepted that liver hepatocytes serve as a primary source for systemic AGT concentrations as the substrate for systemic concentrations of ANG II. Previous studies demonstrated that adipose tissue is a major extra-hepatic source of AGT (2,3,5,8). ANG is also expressed in several other extra-hepatic peripheral tissues, including kidney, adrenal, and brain (3,8). Fur...

Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) -/- mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE-/- mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 ± 6 vs 137 ± 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 ± 0.4 vs 0.9 ± 0.1 %, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation.

Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were bred with AT1aR-floxed mice to generate mice with adipocyte AT1aR deficiency (AT1aR(aP2)). AT1aR mRNA abundance was reduced significantly in both white and brown adipose tissue from AT1aR(aP2) mice compared with nontransgenic littermates (AT1aR(fl/fl)). Adipocyte AT1aR deficiency did not influence body weight, glucose tolerance, or blood pressure in mice fed either LF or high-fat diets. However, LF-fed AT1aR(aP2) mice exhibited striking adipocyte hypertrophy even though total fat mass was not different between genotypes. Stromal vascular cells from AT1aR(aP2) mice differentiated to a lesser extent to adipocytes compared with controls. Conversely, incubation of 3T3-L1 adipocytes with AngII increased Oil Red O staining and increased mRNA abundance of peroxisome proliferator-activated receptor γ (PPARγ) via AT1R stimulation. These results suggest that reductions in adipocyte differentiation in LF-fed AT1aR(aP2) mice resulted in increased lipid storage and hypertrophy of remaining adipocytes. These results demonstrate that AngII regulates adipocyte differentiation and morphology through the adipocyte AT1aR in lean mice.