Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa͞fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean ؉͞؉ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4-to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa͞fa rats, SREBP-1c was 3.4 times higher than in lean ؉͞؉ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa͞fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Upregulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean ؉͞؉ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats. Insulin stimulates hepatic lipid synthesis by selectively upregulating the expression of a lipogenic transcription factor, sterol regulatory element binding protein (SREBP)-1c (1). In insulindeficient rats, SREBP-1c expression is low and is restored almost to normal within 6 h by insulin replacement (1). It is elevated in two insulin-resistant models of leptin deficiency, the ob͞ob mouse and a transgenic mouse model of generalized lipodystrophy (2). Studies in isolated hepatocytes (1, 3, 4) and adipocytes (5) indicate that insulin induces SREBP-1c gene transcription. These reports raise the possibility that increased lipogenesis secondary to leptin unresponsiveness might also be the consequence of overexpression of SREBP-1 in nonadipose tissues. If so, its prevention might protect against lipotoxicity (6), i.e., the disease consequences of overaccumulation of unoxidized lipids in liver, skeletal muscle, pancreatic islets, and myocardium postulated to cause, respectively, insulin resistance (7, 8), noninsulin-dependent diabetes mellitus (9), and heart dysfunction (10).In obese Zucker diabetic fatty (ZDF) rats, ectopic lipid overaccumulation and lipotoxicity occur early in life as the result of a loss-of-function mutation ( fa) in their leptin receptors (11,12). All of the foregoing disease consequences are evident by the age of 14 weeks, provided the rats' diet contains at least 6% fat. Prophylactic treatment with troglitazone (TGZ) of obese, prediabetic ZDF ( fa͞fa) rats prevents the increase in ectopic triacylglycerol (TG) deposition, the insulin resistance (13, 14), the noninsulin-dependent diabetes mellitus (14), and ...

Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. The decline in food intake, body weight, and body fat in old rats was only 25%, 50%, and 16%, respectively, of the young rats. Whereas in young rats plasma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadipocyte factor 1 increased dramatically and leptin mRNA virtually disappeared; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activated receptor alpha, accounting for the reduction in body fat. These hyperleptinemia-induced changes were profoundly reduced in the old rats. On a high-fat diet, old rats consumed 28% more calories than the young and gained 1.5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (SOCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was approximately 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly.

Morbid obesity is the result of massive expansion of white adipose tissue (WAT) and requires recruitment of adipocyte precursor cells and their supporting infrastructure. To characterize the change in the expression profile of the preexisting WAT at the start of obesity, when adipocyte hypertrophy is present but hyperplasia is still minimal, we employed a cDNA subtraction screen for genes differentially expressed in epididymal fat pads harvested 1 wk after the start of a 60% fat diet. Ninety-six genes were upregulated by at least 50% above the WAT of control rats receiving a 4% fat diet. Of these genes, 30 had not previously been identified. Sixteen of the 96 genes, including leptin, adipocyte complement-related protein 30 kDa, and resistin, were predicted to encode a signal peptide. Ten of the 16 had been previously identified in other tissues and implicated in cell growth, proliferation, differentiation, cell cycle control, and angiogenesis. One was a novel gene. Twenty-nine novel fragments were identified. Thus, at the onset of high-fat-diet-induced obesity in rats, adipose tissue increases its expression of factors previously implicated in the expansion of nonadipocyte tissues and of several uncharacterized novel factors. The only one of these thus far characterized functionally was found to promote lipogenesis.

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