Growth hormone and insulin-like growth factor-I in the regulation oflipoprotein lipase in the rat

Abstract

Growth hormone (GH) has profound effects on lipid metabolism. Both body fat mass and lipoprotein metabolism are regulated by GH.Lipoprotein lipase (LPL) is a key enzyme of triglyceride removal from the circulation and hence supply adipose as well as muscle tissueswith fatty acids for storage or as an energy fuel. In the present study, the regulation of GH receptors (GHR) and the GH dependentgrowth factor, insulin-like growth factor-I (IGF-I) expression by GH in adipose tissue of hypophysectomized rats was investigated.Moreover, the effects of GH and IGF-I in the regulation of LPL activity in adipose tissue and muscle tissues were studied in order to getfurther insight into the mechanisms by which GH and IGF-I regulate body fat and lipoprotein metabolism. Hypophysectomized ratswere used. They were given hydrocortisone acetate and L-thyroxine as replacement therapy. In addition, human or bovine recombinantGH or human recombinant IGF-I were given by subcutaneous injections or as a continuous subcutaneous infusion using osmoticminipumps. After 5-7 days of treatment, the rats were killed and the tissues excised. Messenger ribonucleic acid levels in the selectedtissues (GHR, IGF-I and LPL) were quantified by a solution hybridization technique. Lipase activity was measured using assays inwhich radiolabeled triacylglycerol is hydrolyzed and labeled free fatty acids measured. IGF-I, insulin, glucose and free fatty acidconcentrations were quantified using standard methods. Glucose incorporation into lipids in adipose tissue explants or isolatedadipocytes as well as into glycogen in the soleus muscle were studied in vitro. Hypophysectomy resulted in decreased GHR mRNAlevels in adipose tissue of hypophysectomized rats. After a single injection of GH, GHR mRNA was induced within two hours. A GHdose-dependent increase in GHR mRNA levels was found. Northern blot analysis revealed two transcripts of 3.6 kb and of 1.2 kb,which are believed to encode the full length GH receptor and a GH binding protein, respectively. IGF-I mRNA levels decreased inadipose tissue following hypophysectomy. GH treatment dose-dependently increased IGF-I mRNA levels. In vitro, addition of GH toisolated adipocytes increased IGF-I mRNA and the accumulation of IGF-I into the medium. Post-heparin plasma lipoprotein lipase andhepatic lipase (HL) activities decreased after hypophysectomy of female rats. In these experiments, GH was given either as two daily s.cinjections or as a continuous s.c infusion. Irrespective of the mode of administration, LPL and HL activities increased by GH treatment.In adipose tissue, LPL activity was unchanged after hypophysectomy, but was increased by GH treatment. LPL mRNA levels changedin parallel. In the heart and the gastrocnemius muscle, hypophysectomy resulted in decreased LPL activity and GH administrationincreased LPL activity. In the heart LPL activity changed in parallel with LPL mRNA levels, whereas no effect of GH treatment on LPLmRNA levels was found in the gastrocnemius muscle. Finally, the effect of IGF-I treatment on LPL activity was studied. In adiposetissue, IGF-I treatment of hypophysectomized rats reduced LPL activity. No effect of IGF-I treatment on LPL activity in the heart orgastrocnemius muscle was observed. Insulin stimulated glucose incorporation into lipids was reduced in adipose tissue. In the soleusmuscle, glycogen content and insulin stimulated glycogen synthesis increased after IGF-I treatment. In summary, GH interacts andregulates its own receptor in adipose tissue. This interaction results in increased expression and production of IGF-I. GH increases bothLPL and hepatic lipase activities, effects that may be of importance in the regulation of lipoprotein turn-over by GH. IGF-I does notstimulate LPL activities, indicating that the effect of GH on lipoprotein turn-over may not be mediated via IGF-I. On the the other hand,IGF-I inhibited basal and insulin stimulated lipogenesis in adipose tissue and increased glycogen storage in skeletal muscle.