Up-Regulation of Mitochondrial Activity and Acquirement of Brown Adipose Tissue-Like Property in the White Adipose Tissue of Fsp27 Deficient Mice

Abstract

Fsp27, a member of the Cide family proteins, was shown to localize to lipid droplet and promote lipid storage in adipocytes. We aimed to understand the biological role of Fsp27 in regulating adipose tissue differentiation, insulin sensitivity and energy balance. Fsp27 −/− mice and Fsp27/lep double deficient mice were generated and we examined the adiposity, whole body metabolism, BAT and WAT morphology, insulin sensitivity, mitochondrial activity, and gene expression changes in these mouse strains. Furthermore, we isolated mouse embryonic fibroblasts (MEFs) from wildtype and Fsp27 −/− mice, followed by their differentiation into adipocytes in vitro. We found that Fsp27 is expressed in both brown adipose tissue (BAT) and white adipose tissue (WAT) and its levels were significantly elevated in the WAT and liver of leptin-deficient ob/ob mice. Fsp27 −/− mice had increased energy expenditure, lower levels of plasma triglycerides and free fatty acids. Furthermore, Fsp27 −/− and Fsp27/lep double-deficient mice are resistant to diet-induced obesity and display increased insulin sensitivity. Moreover, white adipocytes in Fsp27 −/− mice have reduced triglycerides accumulation and smaller lipid droplets, while levels of mitochondrial proteins, mitochondrial size and activity are dramatically increased. We further demonstrated that BAT-specific genes and key metabolic controlling factors such as FoxC2, PPAR and PGC1α were all markedly upregulated. In contrast, factors inhibiting BAT differentiation such as Rb, p107 and RIP140 were down-regulated in the WAT of Fsp27 −/− mice. Remarkably, Fsp27 −/− MEFs differentiated in vitro show many brown adipocyte characteristics in the presence of the thyroid hormone triiodothyronine (T3). Our data thus suggest that Fsp27 acts as a novel regulator in vivo to control WAT identity, mitochondrial activity and insulin sensitivity.

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…In mouse models, genetic deletion of macrophage PPARγ resulted in increased development of atherosclerosis (Chawla et al, 2001), whereas genetic deletion of PPARα (Tordjman et al, 2001) and PPARδ (Lee et al, 2003) led to reduced atherosclerosis. Similarly, PPARα and PPARγ agonists have been shown to significantly reduce atherosclerotic lesions in mice.…”

“…Similarly, Fsp27-deficient mice have dramatically lower levels of serum TGs and much smaller lipid droplets in their white adipocytes (Nishino et al, 2008;Toh et al, 2008). Fsp27 deficiency results in higher lipolysis rates, especially for basal lipolysis, and leads to a reduction in fat accumulation (Nishino et al, 2008;Toh et al, 2008).…”

“…Fsp27 deficiency results in higher lipolysis rates, especially for basal lipolysis, and leads to a reduction in fat accumulation (Nishino et al, 2008;Toh et al, 2008). Ectopic expression of Fsp27 in 3T3-L1 preadipocytes promotes the formation of significantly larger LDs, and enhances accumulation of total neutral lipids (Puri et al, 2007).…”

Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes

“…Recent studies using mice defi cient in CIDE proteins suggested that this class of protein is closely related to energy balance and obesity (34)(35)(36)(37). In addition, lower levels of CIDEA in human WAT are observed in abdominal obesity, enlarged fat cells, and insulin resistance ( 38,39 ).…”

Negatively‐charged residues in the polar carboxy‐terminal region in FSP27 are indispensable for expanding lipid droplets

“…TAG storage in liver, skeletal muscle and heart is considered to serve as local energy supply. Recently, fat specific protein of 27 kDa (FSP27) was found to be a determinant factor for LD size and also to be critical for large unilocular LD formation in white adipocytes [10][11][12]. However, the precise molecular mechanism by which FSP27 promotes the enlargement of LDs is not understood.…”