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 ...

Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor‐C (VEGF‐C) is a recently described lymphangiogenic factor. Increased expression of VEGF‐C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF‐C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF‐C expression, driven by the rat insulin promoter (Rip), is targeted to β‐cells of the endocrine pancreas. In contrast to wild‐type mice, which lack peri‐insular lymphatics, RipVEGF‐C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic β‐cell tumours that are neither lymphangiogenic nor metastatic. Double‐transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of β‐cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF‐C‐induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.

To determine whether the antidiabetic action of troglitazone (TGZ), heretofore attributed to insulin sensitization, also involves protection of ␤ cells from lipoapoptosis, we treated prediabetic Zucker Diabetic Fatty rats with 200 mg͞kg per day of TGZ. Their plasma-free fatty acids and triacylglycerol fell to 1.3 mM and 111 mg͞dl, respectively, compared with 2.0 mM and 560 mg͞dl in untreated controls. Their islet triacylglycerol content was 34% below controls. In islets of control rats, ␤ cells were reduced by 82% and the islet architecture was disrupted; ␤-cell glucose transporter-2 was absent, 85% of their mitochondria were altered, and they were unresponsive to glucose. In treated rats, the loss of ␤ cells was prevented, as were the loss of ␤ cell glucose transporter-2, the mitochondrial alterations, and the impairment of glucose-stimulated insulin secretion. We conclude that the antidiabetic effect of TGZ in prediabetic Zucker Diabetic Fatty rats involves prevention of lipotoxicity and lipoapoptosis of ␤ cells, as well as improvement in insulin sensitivity.