Poor packaging of fat in adipocytes is associated with high lipolysis, lipotoxicity and insulin resistance. Lipiddroplets (LDs) in adipocytes are distinct intracellular organelles that are the primary storage medium forFFAs as triglycerides (TGs). There is a lack of knowledge of the molecular components of LDs whichdetermine their morphology and TG storing capacity in adipocytes. Thus, there is an urgent need tounderstand the pathways involved in regulating LDs and TG accumulation in adipocytes. We and othersrecently identified that fat specific protein (FSP27, also called CIDEC), is associated with LDs and plays arole in fat metabolism in adipocytes. Expressing FSP27 in cells causes increased TG accumulation andlarger LDs whereas its depletion results in fragmentation of LDs and increased TG hydrolysis. We alsoidentified a mutation in FSP27 which causes partial lipodystrophy and insulin resistance (IR) in humans. Inanother study, we found that FSP27 expression was higher in WAT of insulin sensitive vs. insulin resistantobese humans. Our studies show that FSP27 is a major new modulator of LD morphology and function.Based upon our strong preliminary data, we hypothesize that in human adipocytes FSP27 is a criticalregulator of LD morphology and is required for efficient TG storage. We further hypothesize that FSP27regulates TG storage by decreasing basal lipolysis in adipocytes. Together, these steps will protectadipocytes from FFA mediated IR by sequestering FFAs as TGs in LDs. We propose a detailed mechanisticstudy of structure-function relationships by which FSP27 acts as a multifunctional regulator of LD assembly(Aim 1), TG storage (Aim 2) and insulin sensitivity (Aim 3) in human adipocytes. Our studies will advance thefield by identifying the molecular components of LDs that determine their morphology, and elucidating themechanism(s) involved in TG turnover in adipocytes. Furthermore, these studies will provide tools byidentifying the specific amino acid sequences that could be used as therapeutics for insulin resistance.
Type II diabetes and obesity are pandemic diseases and free fatty acids have an important role in the pathophysiology of these diseases. We have recently identified that fat specific protein 27 (FSP27~ human ortholog CIDEC) is associated with fatty acid metabolism and insulin sensitivity in humans. The key goal of this project is to determine the structure-function relationships that mediate the multiple actions of FSP27 in regulating fat storage and insulin sensitivity in human adipocytes.
| Grahn, Tan Hooi Min; Kaur, Rajween; Yin, Jun et al. (2014) Fat-specific protein 27 (FSP27) interacts with adipose triglyceride lipase (ATGL) to regulate lipolysis and insulin sensitivity in human adipocytes. J Biol Chem 289:12029-39 |
| Singh, Maneet; Kaur, Rajween; Lee, Mi-Jeong et al. (2014) Fat-specific protein 27 inhibits lipolysis by facilitating the inhibitory effect of transcription factor Egr1 on transcription of adipose triglyceride lipase. J Biol Chem 289:14481-7 |
| Lee, Mi-Jeong; Pickering, R Taylor; Puri, Vishwajeet (2014) Prolonged efficiency of siRNA-mediated gene silencing in primary cultures of human preadipocytes and adipocytes. Obesity (Silver Spring) 22:1064-9 |
| Grahn, Tan Hooi Min; Zhang, Yan; Lee, Mi-Jeong et al. (2013) FSP27 and PLIN1 interaction promotes the formation of large lipid droplets in human adipocytes. Biochem Biophys Res Commun 432:296-301 |
