ORONARY HEART DISEASE (CHD) is a major cause of disability and premature death throughout the world. 1 Epidemiological studies have demonstrated an inverse association between physical fitness and the incidence of CHD or allcause mortality in healthy or asymptomatic participants. Physical fitness is typically expressed as cardiorespiratory fitness (CRF) and is assessed by exercise tolerance testing 2 ; however, it is rare for clinicians to consider CRF when evaluating future risk of CHD. 3 A major reason for lack of consideration of CRF as a marker of CHD risk may be that the quantitative association of CRF for cardiovascular risk is not well established. The degree of risk reduc-CME available online at www.jamaarchivescme.com and questions on p 2053.

Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, we generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant HSL allele (HSL؊͞؊) were superficially normal except that the males were sterile because of oligospermia. HSL؊͞؊ mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in HSL؊͞؊ mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in HSL؊͞؊ mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggests the heterogeneity of adipocytes. Despite these morphological changes, HSL؊͞؊ mice were neither obese nor cold sensitive. Furthermore, WAT from HSL؊͞؊ mice retained 40% of triacylglycerol lipase activities compared with the wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.

To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of lipogenic enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were consistently low in both wildtype and SREBP-1 ؊/؊ mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1 ؊/؊ mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refed SREBP-1 ؊/؊ livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these lipogenic enzymes were also strikingly lower in SREBP-1 ؊/؊ mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.Cholesterol and fatty acids are the primary lipids synthesized in liver. However, biosynthetic pathways for cholesterol and fatty acids are under distinct and separate regulation (for a review, see Ref. 1). In contrast to cholesterol synthesis, which is tightly regulated by a feedback system to maintain cellular cholesterol levels, fatty acid synthesis is driven primarily by the availability of carbohydrates and the actions of hormones such as insulin. Despite these different patterns of regulation, recent evidence suggests that both biosynthetic pathways can be controlled by a common family of transcription factors designated sterol regulatory element binding proteins (SREBPs)