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Original Studies |
Endocrinology and Metabolism Unit and Surgery Unit (R.D.), University of Louvain, Faculty of Medicine, UCL 5530, B-1200 Brussels, Belgium
Address all correspondence and requests for reprints to: S. M. Brichard, Unité d’Endocrinologie et Métabolisme, UCL 5530, avenue Hippocrate 55, B-1200 Brussels, Belgium.
The direct role of hormones on leptin synthesis has not yet been
studied in cultured adipose cells or tissue from lean and obese
subjects. Moreover, this hormonal regulation has never been addressed
in human visceral fat, although this site plays a determinant role in
obesity-linked disorders. In this study, we investigated the hormonal
control of ob expression and leptin production in
cultured visceral adipose tissue from lean and obese subjects. We more
particularly focused on the interactions between glucocorticoids and
insulin. We also briefly tackled the role of cAMP, which is still
unknown in man. Visceral (and subcutaneous) adipose tissues from eight
obese (body mass index, 41 ± 2 kg/m2) and nine
nonobese (24 ± 1 kg/m2) subjects were sampled during
elective abdominal surgery, and explants were cultured for up to
48 h in MEM. The addition of dexamethasone to the medium increased
ob gene expression and leptin secretion in a
time-dependent manner. Forty-eight hours after dexamethasone (50
nmol/L) addition, the cumulative integrated ob messenger
ribonucleic acid (mRNA) and leptin responses were, respectively,
approximately 5- and 4-fold higher in obese than in lean subjects.
These responses closely correlated with the body mass index. The
stimulatory effect of the glucocorticoid was also concentration
dependent (EC50 = 
10 nmol/L). Although the maximal
response was higher in obese than in lean subjects, the
EC50 values were roughly similar in both groups. Unlike
dexamethasone, insulin had no direct stimulatory effect on
ob gene expression and leptin secretion. Singularly,
insulin even inhibited the dexamethasone-induced rise in
ob mRNA and leptin release. This inhibition was observed
in both lean and obese subjects, whereas the expected stimulation of
insulin on glucose metabolism and the accumulation of mRNA species for
the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate
dehydrogenase occurred in lean patients only. This inhibitory effect
was already detectable at 10 nmol/L insulin and was also observed in
subcutaneous fat. Although a lowering of intracellular cAMP
concentrations is involved in some of the effects of insulin on adipose
tissue, this cannot account for the present finding, because the
addition of cAMP to the medium also decreased ob mRNA
and leptin secretion (regardless of whether dexamethasone was present).
In conclusion, glucocorticoids, at physiological concentrations,
stimulated leptin secretion by enhancing the pretranslational machinery
in human visceral fat. This effect was more pronounced in obese
subjects due to a greater responsiveness of the ob gene
and could contribute to the metabolic abnormalities associated with
central obesity by para/endocrine actions of hyperleptinemia on
adipocytes and liver. Unlike dexamethasone, insulin had no direct
stimulatory effect on ob gene expression and leptin
secretion, and even prevented the positive response to dexamethasone by
a cAMP-independent mechanism that remained functional despite insulin
resistance.
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