Stimulation of human omental adipose tissue lipolysis by growth hormone plus dexamethasone
Introduction
Fain et al. (1965) reported over 40 years ago that the combination of dexamethasone [Dex] and growth hormone [GH] enhanced lipolysis in rat adipose tissue and this effect appeared to involve ribonucleic acid synthesis. Subsequently, Bergad et al. (1995) reported that GH induction of hepatic serine protease inhibitor 2.1 was mediated by a member of the family of signal transducers and activators of transcription family known as Stat5. Fain et al. (1999) using Stat5b as well as Stat5a/5b double knockout mice reported that the lipolytic action in mouse adipose tissue of growth hormone in the presence of dexamethasone was unaffected in Stat5b knockout mice but was abolished in Stat5a/5b double knockout mice. The current paradigm is that growth hormone binds to a receptor on the cell surface of adipocytes and dimerization of this receptor results in recruitment of JAK-2 kinase to the inner surface of the plasma membrane of adipocytes (Brooks et al., 2008). Stat 5 is phosphorylated on tyrosine residues and enhances transcription of the mRNA for one or more unknown proteins that enhance the breakdown of triacylglycerols in adipocytes. Various possibilities have been suggested with the most recent being hormone-sensitive lipase [HSL] based on studies in rat adipocytes (Yang et al., 2004). Yip and Goodman (1999) had previously reported that growth hormone and dexamethasone affected lipolysis through the Gi α2 protein which was confirmed by Yang et al. (2004), who also found effects of GH on β1 but not β2 adrenergic activation of lipolysis.
It is established that growth hormone promotes protein deposition and reduces fat mass in humans (Scanes, 1995, Jorgensen et al., 2007, Davidson, 1987). The insulin antagonistic effects of GH in humans have been attributed to the activation of lipolysis (Nielsen et al., 2001). Djurhuus et al. (2004) subsequently reported that the administration of growth hormone or a glucocorticoid to humans enhances in vivo lipolysis by subcutaneous adipose tissue after a lag period of approximately 2 h. They found that the effects were independent and additive of growth hormone and glucocorticoids. Efforts to demonstrate a direct lipolytic effect of GH on human subcutaneous adipose tissue have been difficult to demonstrate (Scanes, 1995, Jorgensen et al., 2007, Davidson, 1987, Nielsen et al., 2001) but seen by some (Harant et al., 1994, Ottosson et al., 2000). Another lipolytic agent is interferon β [IFNβ] that stimulates lipolysis in murine in vitro differentiated adipocytes (Feingold et al., 1992). The present studies were designed to determine whether IFNβ, Dex, GH or GH plus Dex enhance lipolysis in explants of visceral omental adipose tissue from morbidly obese women incubated in primary culture for 48 h and whether this was accompanied by changes in the mRNAs for HSL, perilipin, adipose tissue triglyceride lipase [ATGL] and β1-adrenergic receptors [β1-AR].
Section snippets
Subjects
Omental adipose tissue was obtained from morbidly obese, but otherwise, healthy women undergoing either laparoscopic adjustable gastric banding surgery or laparoscopic gastric bypass with Roux-en-y gastroenterostomy surgery for the treatment of morbid obesity. The mean body mass index [BMI] of the morbidly obese women was 46. Approximately half of the women were being treated for hypertension. Exclusion criteria included any history of HIV and/or viral hepatitis positive, chronic coexistent
Results
The combination of 20 nM GH plus 50 nM Dex significantly stimulated lipolysis by 39% when explants of human omental adipose tissue from morbidly obese women were incubated for 48 h [Fig. 1]. There was no lipolytic effect of 2000 units/ml of IFNβ, GH or Dex alone. The 39% increase in lipolysis over 48 by explants of human omental fat due to GH plus Dex was comparable to that seen with 25 nM isoproterenol that enhanced lipolysis by an average of 28 ± 8% as the mean ± S.E.M. of 10 experiments [unpublished
Discussion
The present studies utilized omental adipose tissue that is the predominant form of visceral or abdominal adipose tissue in humans since the clinical feature of GH-mediated fat loss is preferential loss of abdominal fat (Franco et al., 2005, Franco et al., 2007). A stimulation of basal lipolysis could be seen after the addition of GH plus Dex to explants of human omental adipose tissue incubated in vitro. There was also a comparable increase in the accumulation of HSL mRNA at the end of the 48 h
Acknowledgements
Financial support: The Van Vleet Chair of Excellence, University of Tennessee and Zen-Bio Inc supported this research.
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