Glucocorticoid administration : studies on weight regulation and metabolic implications

Long-term treatment with glucocorticoids induces weight gain and increased risk to develop obesity-related metabolic complications like insulin resistance, type 2 diabetes and cardiovascular disease. Glucocorticoids have been suggested to play a role in development of visceral fat accumulation. The similarities between conditions with cortisol excess, for example Cushing's syndrome and the metabolic syndrome are obvious.

In this thesis the main outcome variables are the glucocorticoid effects on eating behaviour and aspects of appetite regulation, adipose tissue secretion and distribution as well as cortisone/cortisol conversion in a clinical setting. The results are based on studies conducted on subjects treated with high doses of prednisolone for shorter periods of time (24 hours and seven days) as well as long-time treatment (twelve months). All subjects were their own controls, allowing disclosure of intra-individual variability. The main findings were that:

*Long-term glucocorticoid treatment causes an increase in food intake in spite of elevated leptin levels. In addition, an association is suggested between unfavourable changes of the eating curve, probably indicating blunted satiety signals, and centralisation of fat depots.

*Short-term treatment with glucocorticoids also causes an increase in food intake, simultaneously with a rise in circulating leptin levels, indicating diminished satiation signalling.

*UCP2 mRNA expression decrease after short-term glucocorticoid exposure, that correlated with increased insulin levels, could promote adipose tissue accumulation. A causal link to the metabolic syndrome is therefore suggested.

*A significant increase in PAI-1 secretion from subcutaneous adipose tissue, following short-term glucocorticoid treatment suggest a possible mechanism for hypercortisolemia in mediating increased risk for cardiovascular disease.

*Impaired 11 beta-hydroxysteroid dehydrogenase 1 expression and an increase of glucocorticoid receptor expression, indicates a regulatory effect of glucocorticoids. An association with reduced feeling of satiation reinforces the suggested glucocorticoid mediated increase in appetite, occurring even after a short treatment period.

List of scientific papers

I. Uddén J, barkeling B, Brismar TB, Bjorntorp P, Berlin M, Brismar K, Rossner S. (2003). Effects of long-term treatment of patients with pulmonary sarcoidosis; leptin levels, eating behaviour and body composition assesments. Journal of Internal Medicine. [Submitted]

II. Udden J, Bjorntorp P, Arner P, Barkeling B, Meurling L, Rossner S (2003). Effects of glucocorticoids on leptin levels and eating behaviour in women. J Intern Med. 253(2): 225-31.
https://pubmed.ncbi.nlm.nih.gov/12542564

III. Udden J, Folkesson R, Hoffstedt J (2001). Downregulation of uncoupling protein 2 mRNA in women treated with glucocorticoids. Int J Obes Relat Metab Disord. 25(11): 1615-8.
https://pubmed.ncbi.nlm.nih.gov/11753580

IV. Udden J, Eriksson P, Hoffstedt J (2002). Glucocorticoid-Regulated Adipose Tissue Secretion of PAI-1, but not IL-6, TNFalpha or Leptin in Vivo. Horm Metab Res. 34(11-12): 698-702.
https://pubmed.ncbi.nlm.nih.gov/12660885

V. Uddén J, Lonn M, Wake D, Walker BR, Barkeling B, Bjornetorp P (2003). Effects of cortisol/cortisone conversion in subcutaneous adipose tissue by 11beta hydroxysteroid dehydrogenase in women after exposure to prednisolone. [Manuscript]