Shulman GI

References (5)

Title : Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop - Goldberg_2018_Circulation_138_305
Author(s) : Goldberg IJ , Reue K , Abumrad NA , Bickel PE , Cohen S , Fisher EA , Galis ZS , Granneman JG , Lewandowski ED , Murphy R , Olive M , Schaffer JE , Schwartz-Longacre L , Shulman GI , Walther TC , Chen J
Ref : Circulation , 138 :305 , 2018
Abstract : Lipid droplets (LDs) are distinct and dynamic organelles that affect the health of cells and organs. Much progress has been made in understanding how these structures are formed, how they interact with other cellular organelles, how they are used for storage of triacylglycerol in adipose tissue, and how they regulate lipolysis. Our understanding of the biology of LDs in the heart and vascular tissue is relatively primitive in comparison with LDs in adipose tissue and liver. The National Heart, Lung, and Blood Institute convened a working group to discuss how LDs affect cardiovascular diseases. The goal of the working group was to examine the current state of knowledge on the cell biology of LDs, including current methods to study them in cells and organs and reflect on how LDs influence the development and progression of cardiovascular diseases. This review summarizes the working group discussion and recommendations on research areas ripe for future investigation that will likely improve our understanding of atherosclerosis and heart function.
ESTHER : Goldberg_2018_Circulation_138_305
PubMedSearch : Goldberg_2018_Circulation_138_305
PubMedID: 30012703

Title : Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes - Morino_2012_Diabetes_61_877
Author(s) : Morino K , Petersen KF , Sono S , Choi CS , Samuel VT , Lin A , Gallo A , Zhao H , Kashiwagi A , Goldberg IJ , Wang H , Eckel RH , Maegawa H , Shulman GI
Ref : Diabetes , 61 :877 , 2012
Abstract : Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underlying factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ~512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator-activated receptor (PPAR)-delta. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-delta activation.
ESTHER : Morino_2012_Diabetes_61_877
PubMedSearch : Morino_2012_Diabetes_61_877
PubMedID: 22368174

Title : CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance - Brown_2010_J.Lipid.Res_51_3306
Author(s) : Brown JM , Betters JL , Lord C , Ma Y , Han X , Yang K , Alger HM , Melchior J , Sawyer J , Shah R , Wilson MD , Liu X , Graham MJ , Lee R , Crooke R , Shulman GI , Xue B , Shi H , Yu L
Ref : J Lipid Res , 51 :3306 , 2010
Abstract : Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in approximately 80-95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels approximately 4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.
ESTHER : Brown_2010_J.Lipid.Res_51_3306
PubMedSearch : Brown_2010_J.Lipid.Res_51_3306
PubMedID: 20802159
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues - Wang_2009_Diabetes_58_116
Author(s) : Wang H , Knaub LA , Jensen DR , Young Jung D , Hong EG , Ko HJ , Coates AM , Goldberg IJ , de la Houssaye BA , Janssen RC , McCurdy CE , Rahman SM , Soo Choi C , Shulman GI , Kim JK , Friedman JE , Eckel RH
Ref : Diabetes , 58 :116 , 2009
Abstract : OBJECTIVE: Skeletal muscle-specific LPL knockout mouse (SMLPL(-/-)) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition. RESEARCH DESIGN AND METHODS: Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL(-/-) and control mice. RESULTS: Nine-week-old SMLPL(-/-) mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL(-/-) mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL(-/-) mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL(-/-) vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL(-/-) mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL(-/-) mice, but peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and interleukin-1beta mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPARgamma mRNAs were reduced. CONCLUSIONS: LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.
ESTHER : Wang_2009_Diabetes_58_116
PubMedSearch : Wang_2009_Diabetes_58_116
PubMedID: 18952837

Title : Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart - Park_2005_Am.J.Physiol.Endocrinol.Metab_289_E30
Author(s) : Park SY , Kim HJ , Wang S , Higashimori T , Dong J , Kim YJ , Cline G , Li H , Prentki M , Shulman GI , Mitchell GA , Kim JK
Ref : American Journal of Physiology Endocrinol Metab , 289 :E30 , 2005
Abstract : Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50-80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.
ESTHER : Park_2005_Am.J.Physiol.Endocrinol.Metab_289_E30
PubMedSearch : Park_2005_Am.J.Physiol.Endocrinol.Metab_289_E30
PubMedID: 15701680
Gene_locus related to this paper: mouse-hslip