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Objective-To clarify the role of very low density lipoprotein (VLDL) and apolipoprotein E (apoE) in adipogenesis, we studied newly developed hyperlipidemic obese (ob/ob;apoE Ϫ/Ϫ ) mice. Because hydrolysis of VLDL is believed to be the major source of adipogenic free fatty acids, a higher plasma level of VLDL in these mice should exaggerate obesity. Methods and Results-When fed a high-fat, high-cholesterol diet, ob/ob;apoE Ϫ/Ϫ mice did not show increased body weight or an increased amount of adipose tissue in spite of increased plasma VLDL levels, whereas ob/ob mice showed an increased body weight and amount of adipose tissue, suggesting that there is a novel apoE-dependent pathway for adipogenesis. In vitro experiments using bone marrow stromal cells and 3T3-L1 cells confirmed this notion. ApoE-deficient VLDL did not induce adipogenesis, whereas normal VLDL induced adipogenesis in these cells. The incubation of apoE-deficient VLDL with recombinant human apoE restored its adipogenic activity. Tetrahydrolipstatin, a lipoprotein lipase inhibitor, did not affect the adipogenic activity of VLDL, suggesting that hydrolysis of VLDL did not play a major role in its effects. In fact, lipid components of VLDL or free fatty acids induced only partial adipogenesis. Key Words: VLDL Ⅲ apolipoprotein E Ⅲ lipoprotein lipase Ⅲ obesity Ⅲ adipogenesis F ree fatty acids (FFAs) generated by the hydrolysis of VLDL by lipoprotein lipase (LPL) have been believed to the major driving force in adipogenesis and the development of obesity. FFAs can regulate various steps of adipogenesis, including the activation of early signals, such as peroxisome proliferator-activated receptor-␥ (PPAR␥), induction of adipocyte-specific genes, and maturation to heterogeneous adipocytes containing different sizes of lipid droplets or metabolic activities. 1,2 LPL, secreted from adipocytes and other cell types, is the rate-limiting enzyme for this process. 3,4 Heparan sulfate proteoglycan, the VLDL receptor, and LDL receptor-related protein (LRP) act as cell surface anchors for LPL. [5][6][7] Deficiency of this enzyme induces severe hypertriglyceridemia in humans and mice. 8,9 Homozygous knockout mice are lipodystrophic and die of hypertriglyceridemia soon after birth. 8 However, the importance of LPL in adipogenesis has been challenged by recent investigations studying various new mouse models and humans. Adipose tissue-specific knockout of LPL resulted in normal adiposity, which was mainly due to increased de novo lipogenesis in adipocytes. 10 Crebbp heterozygous mice show lipodystrophy with a change in the expression of a series of genes related to lipid metabolism, suggesting that adipogenesis is a complex process regulated by different steps. 11 Rodents deficient in leptin or leptin receptors show both obesity and increased activity of fatty acid synthase, suggesting the importance of intrinsic lipogenesis in obesity. 12 Human LPL deficiency and apoC-II deficiency result in impaired hydrolysis of VLDL and chylomicron but are usually associated with no...

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The specification of neural fate in Xenopus embryos has been shown to be under regulation by negative factors. The secreted protein bone morphogenetic protein-4 (BMP4) has been identified as one of these factors: in the early gastrula ectoderm, BMP4 can both inhibit neural fate and induce epidermis. In this study, we show that two other Xenopus BMP genes, BMP2 and BMP7, are endowed with the same types of activities. First, we show that expression of a dominant negative form of the BMP2 ligand, which blocks normal processing of the wild-type ligand, causes neuralization of Xenopus ectoderm. Second, we have isolated the Xenopus BMP2/7 receptor (XALK2) and generated a constitutively active mutant that signals in a ligand-independent manner. We show that signals from the activated BMP2/7 receptor also inhibit neuralization and induce epidermis in dissociated ectoderm cells. Consistent with both findings we show that secreted BMP2 and BMP7 ligands can also mediate neural inhibition and epidermal induction. These results suggest that both BMP2 and BMP7 may be involved independently or together with BMP4 in the inhibition of the neural fate and the onset of the epidermal induction pathway in vivo. This further supports the idea that epidermal induction is due to the effects of multiple signals from heterogeneous BMP genes.