| Authors |
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
|
| Submitted By |
Ira Goldberg on 2/8/2009 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2009 |
| Date Published |
1/1/2009 |
| Volume : Pages |
58(1) : 116 - 124 |
| PubMed Reference |
18952837 |
| 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.
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