In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE ؊/؊ ) and compared with wild-type littermates. Compared with wild-type littermates, ACE ؊/؊ mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE ؊/؊ mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE ؊/؊ mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE ؊/؊ mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.fatty acid metabolism ͉ obesity ͉ ACE knockout mice ͉ glucose tolerance T he renin-angiotensin system (RAS) is important in both cardiovascular and body fluid homeostasis (1-3) and has recently been implicated in obesity and energy balance (see ref.4 for a review). All of the components of the RAS are present in adipose tissue and evidence suggests that this RAS is fully functional and can contribute to the accumulation of fat and to obesity (5-7). Recent studies showed that transgenic mice lacking the precursor peptide, angiotensinogen (AGT), have impaired weight gain and adipose tissue development (8), whereas mice with an overabundance of AGT in adipose tissue have markedly increased fat mass (9).Overexpression of genes associated with the RAS has been reported in human visceral adipose tissue in overweight subjects (10), and polymorphisms of the angiotensin-converting enzyme (ACE) gene have been linked to the incidence of obesity and alterations of body mass index (11,12). ACE plays a key role in the RAS in that it converts angiotensin I to the bioactive peptide angiotensin II (Ang II). Ang II has been identified as a trophic factor in the differentiation of preadipocytes to mature adipocytes (13). There is evidence that administration of ACE inhibitors reduces body weight gain in spontaneously hypertensive rats (14), obese Zucker rats (15), and humans (16). However, some studies have shown that the activity of the RAS is inversely related to the gain of body weight....

Interview group respondents were more likely to give top ranking responses to questions on service satisfaction and symptom control. Conclusions-Postal questionnaires are an acceptable alternative to interviews in retrospective post-bereavement surveys of care for the dying, at least in terms of response rate and response bias. However, the increased costs of interview surveys need to be balanced against the fact that postal questionnaires result in more missing data, and possibly less reliable answers to some questions. Caution is needed in combining results from the two data collection methods as interview respondents gave more positive answers to some questions.

Background-Addition of up to 15.0 g/d salt to the diet of chimpanzees caused large rises in blood pressure, which reversed when the added salt was removed. Effects of more modest alterations to sodium intakes in chimpanzees, akin to current efforts to lower sodium intakes in the human population, are unknown. Methods and Results-Sodium intakes were altered among 17 chimpanzees in Franceville, Gabon, and 110 chimpanzees in Bastrop, Tex. In Gabon, chimpanzees had a biscuit diet of constant nutrient composition except that the sodium content was changed episodically over 3 years from 75 to 35 to 120 mmol/d. In Bastrop, animals were divided into 2 groups; 1 group continued on the standard diet of 250 mmol/d sodium for 2 years, and sodium intake was halved for the other group. Lower sodium intake was associated with lower systolic, diastolic, and mean arterial blood pressures in Gabon (2-tailed PϽ0.001, unadjusted and adjusted for age, sex, and baseline weight) and Bastrop (PϽ0.01, unadjusted; Pϭ0.08 to 0.10, adjusted), with no threshold down to 35 mmol/d sodium. For systolic pressure, estimates were Ϫ12.7 mm Hg (95% confidence interval, Ϫ16.9 to Ϫ8.5, adjusted) per 100 mmol/d lower sodium in Gabon and Ϫ10.9 mm Hg (95% confidence interval, Ϫ18.9 to Ϫ2.9, unadjusted) and Ϫ5.7 mm Hg (95% confidence interval, Ϫ12.2 to 0.7, adjusted) for sodium intake lower by 122 mmol/d in Bastrop. Baseline systolic pressures higher by 10 mm Hg were associated with larger falls in systolic pressure by 4.3/2.9 mm Hg in Gabon/Bastrop per 100 mmol/d lower sodium. Conclusions-These findings from an essentially single-variable experiment in the species closest to Homo sapiens with high intakes of calcium and potassium support intensified public health efforts to lower sodium intake in the human population.

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Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine-and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C-adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were upregulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.

Relaxin is well known for its actions on collagen remodeling. To improve our understanding of the physiologic role(s) of relaxin, the relaxin gene-knockout (RLX-KO) mouse was established by our group and subsequently phenotyped. Pregnant RLX-KO mice underwent inadequate development of the pubic symphysis as well as the mammary glands and nipples compared to wild-type mice, thus preventing lactation. Later studies showed that these deficiencies were associated with increased collagen, primarily in the nipple and vagina. Analysis of male RLX-KO mice also demonstrated inadequate reproductive tract development. The testis, epididymis, and prostate of RLX-KO mice showed delayed tissue maturation and growth associated with increased collagen deposition. In nonreproductive tissues, an age-related increase in interstitial collagen (fibrosis) was also detected in the lung, heart, and kidneys of RLX-KO mice and was associated with organ dysfunction. From 6-9 months of age and onwards, all organs of RLX-KO mice, particularly male mice, underwent progressive increases in tissue weight and collagen content (all P < .05) compared with wild-type animals. The increased fibrosis contributed to bronchiole epithelium thickening and alveolar congestion (lung), atrial hypertrophy and increased ventricular chamber stiffness (heart) in addition to glomerulosclerosis (kidney). Treatment of RLX-KO mice with recombinant human relaxin in early and developed stages of fibrosis caused the reversal of collagen deposition in the lung, heart, and kidneys. Together, these findings suggest that relaxin is a naturally occurring inhibitor of collagen deposition during normal development, aging, and pregnancy and can be used to prevent the progression of fibrosis.

Although the AGT and ACE genes are fundamental determinants of angiotensin and bradykinin peptide levels, compensatory mechanisms attenuate the effect of modest change in AGT and ACE gene expression on the levels of these peptides. Identification of these compensatory mechanisms may provide new candidate genes for investigation in humans.

Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (AgtϪ/Ϫ mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in AgtϪ/Ϫ mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in AgtϪ/Ϫ mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both AgtϪ/Ϫ and WT mice during the hour following injection. As well, AgtϪ/Ϫ mice drank appropriate volumes of water following water deprivation for 7 h. However, AgtϪ/Ϫ mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both AgtϪ/Ϫ mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in AgtϪ/Ϫ mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.