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.
Highlights
Obesity, representing excess amount of body fat, develops as a result of a positive energy balance when energy intake exceeds that of metabolic expenditure
Using Fsp27 antibody, we checked the subcellular localization of Fsp27 in differentiated 3T3-L1 cells and observed that a fraction of Fsp27 was co-localized with lipid droplet specific marker Perilipin (Fig. 1D), consistent with previous observation that overexpression of GFP-Fsp27 fusion protein is targeted to lipid droplet [31,32]
We found that total lipid in gonadal white fat (GWAT) pad was reduced by almost 6 fold, which strongly suggests that the reduction in fat pad size observed in white adipose tissue (WAT) of Fsp272/2 mice is a result of decreased lipid content in the adipocytes
Summary
Obesity, representing excess amount of body fat, develops as a result of a positive energy balance when energy intake exceeds that of metabolic expenditure. WAT and BAT both express a set of genes that regulates lipolysis, fatty acid metabolism, triacylglyceride (TAG) storage and insulin sensitivity [2,3], BAT is known to be functionally more important as a thermogenic tissue [4]. It expresses a unique protein, uncoupling protein 1 (Ucp1), which functions to uncouple oxidative phosphorylation and converting this proton gradient energy into heat to maintain normal body temperature. PGC-1a has been shown to coordinate multiple physiological cues for mitochondrial biogenesis and activity [13]
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