1. Skeletal Muscle–Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues
- Author
-
Dae Young Jung, Hong Wang, Robert H. Eckel, Shaikh M. Rahman, Jacob E. Friedman, Hwi Jin Ko, Ira J. Goldberg, Rachel C. Janssen, Carrie E. McCurdy, Leslie A. Knaub, Jason K. Kim, Alison M. Coates, Dalan R. Jensen, Gerald I. Shulman, Cheol Soo Choi, Eun-Gyoung Hong, Becky A. de la Houssaye, Wang, Hong, Knaub, Leslie A, Jensen, Dalan R, Jung, Dae Young, Hong, Eum-Gyoung, Ko, Hwi-Jin, Coates, Alison M, Goldberg, Ira J, de la Houssaye, Becky, Janssen, Rachel C, McCurdy, Carrie E, Rahman, Shaikh M, Choi, Cheol Soo, Shulman, Gerald I, Kim, Jason K, Friedman, Jacob E, and Eckel, Robert H
- Subjects
Blood Glucose ,Male ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Fats ,Mice ,Absorptiometry, Photon ,0302 clinical medicine ,Insulin ,Mice, Knockout ,key metabolic tissues ,2. Zero hunger ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Glucose clamp technique ,Lipids ,medicine.anatomical_structure ,Liver ,Body Composition ,Cytokines ,Obesity Studies ,Signal Transduction ,insulin ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Biology ,03 medical and health sciences ,Insulin resistance ,Commentaries ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,RNA, Messenger ,skeletal muscle ,Muscle, Skeletal ,Liver X receptor ,030304 developmental biology ,Insulin-like growth factor 1 receptor ,Skeletal muscle ,Glucose Tolerance Test ,medicine.disease ,Lipoprotein Lipase ,Insulin receptor ,Endocrinology ,Glucose Clamp Technique ,biology.protein ,Insulin Resistance - 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)-γ coactivator-1α and interleukin-1β mRNAs were higher, and stearoyl–coenzyme A desaturase-1 and PPARγ 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.
- Published
- 2008
- Full Text
- View/download PDF