Abstract
To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.
Highlights
I.e. excessive growth hormone (GH) production secondary to a pituitary adenoma, is a rare condition with an annual incidence of 3 patients per million [1]
In this study we have described a transcriptional signature in adipose tissue from subjects with acromegaly
We identified 418 adipose tissue genes altered in acromegaly patients
Summary
I.e. excessive growth hormone (GH) production secondary to a pituitary adenoma, is a rare condition with an annual incidence of 3 patients per million [1]. Insulin resistance, presenting as diabetes or impaired glucose tolerance, is found in most acromegalic patients [3], and contributes to the enhanced morbidity [4]. Induction of STAT5 tyrosine phosphorylation and IGF1 mRNA expression has been detected in human subcutaneous adipose tissue biopsies taken after acute GH administration [7]. Subcutaneous adipocytes extracted from acromegalic patients are insulin resistant ex vivo, and after a glucose tolerance test there was 50% less insulin binding to its receptor and markedly decreased insulin-related anti-lipolytic activity [8]. In vivo measurement in humans detected GH-induced lipolysis in subcutanous adipose tissue [9]. Microarray of gene expression has been published for subcutaneous adipose tissue biopsies before and after one year of GH treatment in GH deficient patients [11]
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