To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-␣. Levels of ceramide, a mediator of apoptosis, were 2-3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids. The recent increase in juvenile-onset obesity in the United States (1) predicts that the next generation of obese Americans will have been obese longer than ever before. This portends a higher prevalence of time-dependent complications of the disease, such as insulin resistance, non-insulin-dependent diabetes mellitus, hypertension, coronary artery disease, and other cardiac disorders. The etiology of these complications, which are often grouped together under the term ''metabolic syndrome X'' (2), is not known.We have proposed that the excessive deposition of triacylglycerol (TG) in nonadipose tissues (steatosis) enlarges the intracellular pool of fatty acyl-CoA, thereby providing substrate for nonoxidative metabolic pathways, such as ceramide synthesis, that lead to cell dysfunction and death through apoptosis (3). It seemed possible that this sequence of events, established in the pancreatic islets of genetically obese Zucker Diabetic Fatty (ZDF) rats ( fa͞fa), could also take place in other tissues such as the heart. Obesity-related heart disease, the most serious complication of human obesity, generally is attributed to coexisting disorders such as coronary artery disease and hypertension. Cardiac dysfunction, arrhythmias, cardiomyopathy, and congestive heart failure are seldom ascribed to the direct consequences of obesity, i.e., fatty acid (FA) overload of cardiac myocytes, although the literature does contain clinical reports of cardiomyopathy of obesity that can be reversed by weight loss (4).This study was designed to test the possibility that the same metabolic abnormalities that cause lipotoxicity and lipoapoptosis in the pancreatic ␤ cells of obese rats (3) might also compromise the function and viability of their myocardial cells. We used rats with obesity resulting from a loss-of-function mutation in the leptin receptor (5, 6), the ZDF ( fa͞fa) rat. We observed in their fat-laden hearts evidence of lipoapoptosis accompanied by a profound loss of cardiac function. These abnormalities were completely prevented by antisteatotic therapy. The striking benefit of such therapy on cardiac function in obese rats warrants an effort to determine whether a counterpart of this disorder ...

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early ␤ cell compensation for insulin resistance (4-fold ␤ cell hyperplasia) followed by decompensation (>50% loss of ␤ cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3-and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokineinduced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C 2 -Ceramide without FFA induced DNA laddering, but fumonisin B 1 , a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [ H]Palmitate incorporation in [3 H]ceramide in ZDF islets was twice that of controls, but [ 3 H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, ␤ cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.

Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and ␣ 4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for ␣ V ␤ 3. In functional studies, ␣ V ␤ 3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing ␣ 4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation. ( J. Clin. Invest. 1997.