Adipose tissue expresses components of the renin-angiotensin system (RAS). Angiotensin converting enzyme (ACE2), a new component of the RAS, catabolizes the vasoconstrictor peptide ANG II to form the vasodilator angiotensin 1-7 [ANG-(1-7)]. We examined whether adipocytes express ACE2 and its regulation by manipulation of the RAS and by high-fat (HF) feeding. ACE2 mRNA expression increased (threefold) during differentiation of 3T3-L1 adipocytes and was not regulated by manipulation of the RAS. Male C57BL/6 mice were fed low-(LF) or high-fat (HF) diets for 1 wk or 4 mo. At 1 wk of HF feeding, adipose expression of angiotensinogen (twofold) and ACE2 (threefold) increased, but systemic angiotensin peptide concentrations and blood pressure were not altered. At 4 mo of HF feeding, adipose mRNA expression of angiotensinogen (twofold) and ACE2 (threefold) continued to be elevated, and liver angiotensinogen expression increased (twofold). However, adipose tissue from HF mice did not exhibit elevated ACE2 protein or activity. Increased expression of ADAM17, a protease responsible for ACE2 shedding, coincided with reductions in ACE2 activity in 3T3-L1 adipocytes, and an ADAM17 inhibitor decreased media ACE2 activity. Moreover, ADAM17 mRNA expression was increased in adipose tissue from 4-mo HF-fed mice, and plasma ACE2 activity increased. However, HF mice exhibited marked increases in plasma angiotensin peptide concentrations (LF: 2,141 Ϯ 253; HF: 6,829 Ϯ 1,075 pg/ml) and elevated blood pressure. These results demonstrate that adipocytes express ACE2 that is dysregulated in HF-fed mice with elevated blood pressure compared with LF controls.

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...

nikouris F, English VL, Cassis LA. Administration of 17␤-estradiol to ovariectomized obese female mice reverses obesityhypertension through an ACE2-dependent mechanism. Am J Physiol Endocrinol Metab 308: E1066 -E1075, 2015. First published April 14, 2015 doi:10.1152/ajpendo.00030.2015-We recently demonstrated that female mice are resistant to the development of obesity-induced hypertension through a sex hormone-dependent mechanism that involved adipose angiotensin-converting enzyme 2 (ACE2). In this study, we hypothesized that provision of 17␤-estradiol (E2) to ovariectomized (OVX) high-fat (HF)-fed female hypertensive mice would reverse obesity-hypertension through an ACE2-dependent mechanism. Pilot studies defined dose-dependent effects of E2 in OVX female mice on serum E2 concentrations and uterine weights. An E2 dose of 36 g/ml restored normal serum E2 concentrations and uterine weights. Therefore, HF-fed OVX female Ace2and Ace2 Ϫ/Ϫ mice were administered vehicle or E2 (36 g/ml) for 16 wk. E2 administration significantly decreased body weights of HF-fed OVX female Ace2 ϩ/ϩ and Ace2 Ϫ/Ϫ mice of either genotype. At 15 wk, E2 administration decreased systolic blood pressure (SBP) of OVX HF-fed Ace2 ϩ/ϩ but not Ace2 Ϫ/Ϫ females during the light but not the dark cycle. E2-mediated reductions in SBP in Ace2 ϩ/ϩ females were associated with significant elevations in adipose ACE2 mRNA abundance and activity and reduced plasma ANG II concentrations. In contrast to females, E2 administration had no effect on any parameter quantified in HF-fed male hypertensive mice. In 3T3-L1 adipocytes, E2 promoted ACE2 mRNA abundance through effects at estrogen receptor-␣ (ER␣) and resulted in ER␣-mediated binding at the ACE2 promoter. These results demonstrate that E2 administration to OVX females reduces obesity-induced elevations in SBP (light cycle) through an ACE2-dependent mechanism. Beneficial effects of E2 to decrease blood pressure in OVX obese females may result from stimulation of adipose ACE2.17␤-estradiol; blood pressure; ovariectomy; renin-angiotensin system THE PREVALENCE OF HYPERTENSION has consistently risen in the United States largely due to the increasing prevalence of obesity. Data from the most recent National Health and Nutrition Examination Survey (NHANES) demonstrate that the prevalence of hypertension is rising at a faster rate in females than in males (6). It is generally well accepted, based on data from cross-sectional studies, that adult males are at a higher risk to develop hypertension than females until after menopause, when female prevalence of both obesity and hypertension increases markedly (27,28). Mechanisms for the role of menopause in the increasing prevalence of hypertension in females, or for the faster rise in hypertension prevalence in females compared with males are unclear.An activated renin-angiotensin system (RAS) has been suggested to contribute to the development of experimental and human obesity-induced hypertension (2,9,12,14). Indeed, recent studies from our laboratory demonstrate...

BackgroundCoplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss in obese mice. The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear.ObjectivesIn this study we tested the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhRs) to promote adipose inflammation and impair glucose homeostasis in lean mice and in obese mice during weight loss.Methods and ResultsPCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)–fed control (AhRfl/fl) mice but not in adipocyte AhR–deficient mice (AhRAdQ). Unexpectedly, AhRAdQ mice exhibited increased fat mass when fed a standard LF or high fat (HF) diet. In mice fed a HF diet, both genotypes became obese, but AhRAdQ mice administered vehicle (VEH) exhibited increased body weight, adipose mass, adipose inflammation, and impaired glucose tolerance compared with AhRfl/fl controls. Impairment of glucose homeostasis in response to PCB-77 was not observed in obese mice of either genotype. However, upon weight loss, AhRfl/fl mice administered PCB-77 exhibited increased abundance of adipose tumor necrosis factor-α (TNF-α) mRNA and impaired glucose homeostasis compared with those administered VEH. In contrast, PCB-77 had no effect on TNF-α or glucose homeostasis in AhRAdQ mice exhibiting weight loss.ConclusionsOur results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice. Moreover, deficiency of AhR in adipocytes augmented the development of obesity, indicating that endogenous ligand(s) for AhR regulate adipose homeostasis.CitationBaker NA, Shoemaker R, English V, Larian N, Sunkara M, Morris AJ, Walker M, Yiannikouris F, Cassis LA. 2015. Effects of adipocyte aryl hydrocarbon receptor deficiency on PCB-induced disruption of glucose homeostasis in lean and obese mice. Environ Health Perspect 123:944–950; http://dx.doi.org/10.1289/ehp.1408594