The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancerbinding protein δ (C/EBPδ), C/EBPα, and PPARγ coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.
We have previously characterized an activity from human plasma that markedly stimulates triglyceride synthesis in cultured human skin fibroblasts and human adipocytes. Based on its in vitro activity we named the active component acylation stimulating protein (ASP). The molecular identity of the active serum component has now been determined. NH2-terminal sequence analysis, ion spray ionization mass spectroscopy, and amino acid composition analysis all indicate that the active purified protein is a fragment of the third component of plasma complement, C3a-desArg. As well, reconstitution experiments with complement factors B, D, and complement C3, the components necessary to generate C3a, have confirmed the identity of ASP as C3a. ASP appears to be the final effector molecule generated by a novel regulatory system that modulates the rate of triglyceride synthesis in adipocytes. (J. Clin. Invest. 1993.
Objective-Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism. Methods and Results-At 6 months of age, Pcsk9Ϫ/Ϫ mice accumulated Ϸ80% more visceral adipose tissue than wild-type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9 Ϫ/Ϫ Ldlr Ϫ/Ϫ mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9 Ϫ/Ϫ males and females exhibit 4-and Ϸ40-fold higher cell surface levels of very-low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9 Ϫ/Ϫ females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to Ϸ50-fold higher levels of perigonadal VLDLR. Key Words: PCSK9 Ⅲ VLDL receptor Ⅲ adipose tissue metabolism Ⅲ fatty acid uptake Ⅲ proprotein convertase P roprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the family of proprotein convertases (encoded by the genes PCSK1 to PCSK9) that share identity with subtilisin and kexin. 1 The first 8 members of the family cleave protein precursors of hormones, growth factors, receptors, and transmembrane transcription factors that transit through or reside in the secretory pathway. 2 In contrast, PCSK9 has no known substrates but itself. It undergoes an autocatalytic cleavage of its N-terminal prosegment, 1,3 which remains trapped in the catalytic pocket. 4 PCSK9 shortens the half-life of the low-density lipoprotein receptor (LDLR), 5 a process independent of its catalytic activity. 6 Gain-of-function mutations in the PCSK9 gene lead to autosomal dominant hypercholesterolemia, 7 as do mutations in the LDLR and APOB genes. Other PCSK9 mutations or polymorphisms responsible for loss of function result in hypocholesterolemia. 8 PCSK9 is highly expressed in the liver, 1 where it binds the LDLR and promotes its internalization and degradation in endosomal/lysosomal compartments. 5 Thus, mice lacking PCSK9 (Pcsk9 Ϫ/Ϫ ) exhibit a 2-to 3-fold increase of the LDLR protein in liver homogenates, and a substantial accumulation of the receptor at the hepatocyte cell surface. 9,10 This leads to hypocholesterolemia (Ϫ40%), with a Ϸ5-fold drop in low-density lipoprotein (LDL) cholesterol levels. In humans, where 70% of cholesterol is associated with LDLs, versus only 30% in mice, the hypocholesterolemia due to PCSK9 deficiency is even more dramatic. Two women lacking functional PCSK9 exhibited LDL cholesterol levels of Ϸ0.4 mmol/L (15 mg/dL). 11,12 PCSK9 is now considered a promising target to treat hypercholesterolemia and prevent coronary heart disease. Conclusion-InHuman PCSK9 is abundant in plasma, 13 and analysis of mice tha...
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