Muscle-specific deletion of signal transducer and activator of transcription 5 augments lipid accumulation in skeletal muscle and liver of mice in response to high-fat diet
- 410 Downloads
Growth hormone (GH) controls liver metabolism through the transcription factor signal transducer and activator of transcription 5 (STAT5). However, it remains to be fully understood to what extent other GH/STAT5 target tissues contribute to lipid and glucose metabolism. This question was now addressed in muscle-specific STAT5 knockout (STAT5 MKO) mice model.
Changes in lipid and glucose metabolism were investigated at physiological and molecular levels in muscle and liver tissues of STAT5 MKO mice under normal diet or high-fat diet (HFD) conditions.
STAT5 MKO mice exhibited an increased intramyocellular lipid (IMCL) accumulation in the quadriceps in HFD group. Decreased lipolytic hormone-sensitive lipase transcript levels may contribute to the increased IMCL accumulation in STAT5 MKO mice. STAT5 MKO induced hepatic lipid accumulation without deregulated STAT5 signaling. The upregulation of lipoprotein lipase and Cd36 mRNA levels, an increased trend of very low-density lipoprotein receptor mRNA levels, and elevated circulating concentrations of free fatty acid, triglyceride, and total cholesterol support the increase in hepatic lipid accumulation.
STAT5 MKO in conjunction with a HFD deregulated both lipid and glucose metabolism in skeletal muscle, and this deregulation induced hepatic fat accumulation via increased circulating glucose, FFA, and TG concentrations. Our study emphasizes that muscle-specific STAT5 signaling is important for balancing lipid and glucose metabolism in peripheral tissues, including muscle and liver and that the deregulation of local STAT5 signaling augments HFD-induced lipid accumulation in both muscle and liver.
KeywordsSTAT5 muscle deletion Lipid and glucose metabolism Intramyocellular lipid accumulation Hepatic lipid accumulation
Free fatty acid
Insulin-like growth factor 1
Increased intramyocellular lipid
Low-density lipoprotein receptor
Oil Red O
Signal transducers and activators of transcription 5
- STAT5 fl/fl
- STAT5 MKO
Muscle-specific STAT5 knockout
Very low-density lipoprotein receptor
The present study was supported by grants from the National Research Laboratory Program (ROA-2007-0056702) through the NRF funded by the Ministry of Education, Science, and Technology and the Next-Generation BioGreen 21 Program (No. PJ01114001), Rural Development Administration, Republic of Korea.
Compliance with ethical standards
Conflict of interest
- 8.Oscarsson J, Ottosson M, Eden S (1998) Effects of growth hormone on lipoprotein lipase and hepatic lipase. J Endocrinol Invest 22:2–9Google Scholar
- 13.Giustina A, Veldhuis JD (1998) Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human 1. Endocr Rev 19:717–797Google Scholar
- 17.Truett G, Heeger P, Mynatt R, Truett A, Walker J, Warman M (2000) Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). Biotechniques 29(52):54Google Scholar
- 18.Folch J, Lees M, Sloane-Stanley G (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509Google Scholar
- 25.Barbour LA, Rahman SM, Gurevich I, Leitner JW, Fischer SJ, Roper MD, Knotts TA, Vo Y, McCurdy CE, Yakar S (2005) Increased P85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. J Biol Chem 280:37489–37494CrossRefGoogle Scholar
- 28.Johannsson G, Mårin P, Lönn L, Ottosson M, Stenlöf K, Björntorp P, Sjöström L, Bengtsson BA (1997) Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab 82:727–734Google Scholar
- 33.Bredella MA, Torriani M, Thomas BJ, Ghomi RH, Brick DJ, Gerweck AV, Miller KK (2009) Peak growth hormone-releasing hormone-arginine-stimulated growth hormone is inversely associated with intramyocellular and intrahepatic lipid content in premenopausal women with obesity. J Clin Endocrinol Metab 94:3995–4002CrossRefGoogle Scholar
- 36.Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD (2002) Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 87:5649–5657CrossRefGoogle Scholar