The inhibition of growth hormone
secretion presented in obesity is not
mediated by the high leptin levels:
A study in human leptin deficiency patients
GH secretion is regulated by hypothalamic
and peripheral hormones under a very
complex interplay. Superimposed on this
regulation, signals of a metabolic nature
connect GH secretion with the metabolic
and energetic homeostasis of a given
individual. GH secretion is enhanced
in malnutrition and is severely impeded
in obesity, but no information is available
to explain why GH secretion is severely
impeded or blocked in excess adiposity.
Obesity is associated with high plasma
levels of leptin, and leptin participates
at the hypothalamic and pituitary levels
in the regulation of GH secretion. Thus,
it has been postulated that the inhibitory
action of obesity on GH discharge may
be mediated by excess leptin levels.
The only situation in which obesity
does not parallel leptin values is the
rare case of morbid obesity due to leptin
deficiency caused by missense mutation
of the leptin gene. To understand the
causes of GH blockade presented in obesity,
patients with both homozygous and heterozygous
mutations of the leptin gene and matched
controls for both sex and body mass
index (BMI) were studied. Three homozygous
and 5 heterozygous patients with leptin
gene mutations as well as 13 control
subjects were studied. In all subjects
basal levels of leptin and GH values
stimulated by the combined administration
of GHRH plus GH-releasing peptide-6
(GHRP-6) were analyzed. To analyze the
effects of obesity and leptin levels,
5 groups were designed, all them matched
by sex and adiposity. The number of
subjects (n), leptin levels in micrograms
per liter, and adiposity in BMI were
as follows: nonobese subjects: n = 5,
BMI = 22.1 ± 0.9 kg/m2, leptin = 5.4
± 0.9; heterozygous patients: n = 5,
BMI = 27.0 ± 1.0 kg/m2, leptin = 2.3
± 0.1; controls for the heterozygous
group: n = 5, BMI = 24.7 ± 1.1 kg/m2,
leptin = 5.7 ± 1.2; homozygous patients:
n = 3, BMI = 54.4 ± 0.2 kg/m2, leptin
= 1.0 ± 0.2; and controls for the homozygous
group: n = 3, BMI = 50.3 ± 2.0 kg/m2,
leptin = 35.0 ± 6.6. In these matched
groups, the GHRH- and GHRP-6-stimulated
GH secretion (mean peak ± SE; micrograms
per liter) was: nonobese, 86.8 ± 8.9
[significantly higher than heterozygous
(28.6 ± 4.9) and control for heterozygous
(39.9 ± 10.4)]; homozygous group, 9.4
± 3.0; control for homozygous, 9.3 ±
1.0 (significantly lower than the heterozygous,
control for heterozygous, and nonobese
groups). Hence, it appeared that GH
discharge was negatively conditioned
by adiposity and was not influenced
by leptin levels. To further analyze
this observation, a correlation analysis
showed that GH peaks were negatively
correlated with BMI in the 13 control
subjects as well as in the 8 leptin-deficient
patients. On the contrary, the GH peaks
were negatively correlated with leptin
levels in controls, but showed the opposite
pattern in homo- and heterozygous patients.
In conclusion, the GH secretion blockade,
which is characteristic of obese states,
is due to adiposity or some factor linked
to adiposity, but not to elevated plasma
leptin levels.
Ozata
M et al. J Clin Endocrinol and Metabol
2003; 88: 312-316
