Adiponectin concentrations in rodents and humans are sexually dimorphic, with higher concentrations observed in females compared with males. This appears to be due to a selective increase in the HMW oligomer of the hormone.35
These differences develop during puberty and are a result of inhibition of adiponectin production by circulating androgens.154
In mice, HMW adiponectin concentrations are increased by castration and are decreased by testosterone replacement,155
and testosterone replacement therapy significantly reduces adiponectin concentrations in hypogonadal men.156
Studies in 3T3-L1 adipocytes indicate that testosterone-mediated decreases in adiponectin secretion are due to enhanced intracellular retention of HMW adiponectin.155
Adiponectin concentrations are stable throughout the menstrual cycle.157
During pregnancy, however, both adiponectin mRNA expression and circulating adiponectin concentrations decline during the third trimester158
when insulin sensitivity is reduced. This may be a mechanism to ensure greater nutrient availability for the developing fetus.160
Reduced adiponectin concentrations during pregnancy do not appear to be attributable to central fat accumulation and weight gain,159
rather, they are likely to result from inhibition by prolactin, which decreases adiponectin content and secretion in cultured human adipocytes and adipose tissue.159,161
Human adipocytes express prolactin receptors,159,162
and elevated prolactin levels in humans have been associated with insulin resistance.163
Support for this inverse relationship has also been obtained in mice: female, but not male, transgenic mice overexpressing prolactin have reduced adiponectin levels.161
Interestingly, adiponectin concentrations are not increased in prolactin receptor–knockout mice,161
suggesting that this particular pathway may exist to favor the suppression of adiponectin, and thereby ensure fetal growth and development.
Adiponectin mRNA expression and secretion in human adipocytes are also inhibited by glucocorticoids.164
In healthy subjects, similarly, acute intravenous administration of 25 mg hydrocortisone transiently decreased adiponectin by approximately 25% after one hour.165
This effect may be dose-dependent, however, as no changes of adiponectin were observed in men treated for 5 days with 3 mg dexamethasone.166
Excessive endogenous glucocorticoid production (Cushing disease) is associated with central obesity and insulin resistance, conditions under which adiponectin concentrations would already be expected to be reduced. However, at the present time, there are no convincing data to suggest that adiponectin levels are reduced in Cushing patients, independently of obesity.165
In fact, Libè et al.167
reported that there were no differences in adiponectin concentrations between normal-weight Cushing patients and BMI-matched control subjects with similar levels of insulin resistance, and adiponectin concentrations did not change after treatment of the disease with transsphenoidal resection of the pituitary adenomas.
The discrepant effects of glucocorticoids on adiponectin observed between in vivo
and in vitro
studies might possibly be resolved by considering the effects of intracellular steroid metabolism, which appears to be an important determinant of glucocorticoid action. 11β
hydroxysteroid dehydrogenase type 1 (11β
HSD-1) regulates intracellular glucocorticoid levels by converting inactive cortisone to active cortisol, and its activity is elevated in subcutaneous adipose tissue from obese subjects.168
HSD-1 may indirectly regulate adiponectin gene transcription, as adipose-specific overexpression of this enzyme in transgenic mice decreased adiponectin mRNA in mesenteric adipose tissue.169
Conversely, knockout of 11β
HSD-1 in all tissues was associated with increased adiponectin mRNA expression in epididymal fat, although not in visceral mesenteric fat.170
Plasma adiponectin concentrations were not measured in either of these mouse studies, however, so the contribution of local glucocorticoid action in regulating circulating adiponectin concentrations remains to be determined.
Adiponectin may also be inhibited by growth hormone (GH). Adiponectin secretion in cultured explants of human adipose tissue is reduced by incubation with GH, and GH-overexpressing transgenic mice of both sexes have lower circulating adiponectin concentrations than wild-type littermates.161
This effect appears to be independent of energy balance and adiposity, as GH-overexpressing transgenic mice have reduced body fat and are resistant to diet-induced weight gain on a high-fat diet,171
conditions when circulating adiponectin concentrations would be expected to be elevated. The inverse relationship between GH and adiponectin in mice is further supported by the observation that GH receptor deficiency is associated with increased adiponectin concentrations in both sexes.161
The underlying mechanism has been recently shown to involve GH-mediated increases in the expression of the p85 subunit of phosphatidylinositol 3-kinase (PI3K), a negative regulator of insulin signaling, in adipose tissue.172
In humans, however, there is presently a lack of consensus on whether elevated GH levels (such as in acromegaly) are associated with reduced adiponectin concentrations.173–176
There is one positive report, however, of patients with acromegaly having low adiponectin levels that were reversed following GH-lowering therapy.177
However, treatment of HIV-associated lipodystropy patients with recombinant human GH increased circulating adiponectin by approximately 20% and the increase of adiponectin was correlated with increases of HDL cholesterol.178
Adiponectin synthesis and secretion also appear to be inhibited by activation of the sympathetic nervous system. Adiponectin gene expression in human visceral adipose tissue is inhibited by β
Similarly, in both mouse adipose tissue explants and in vivo, β
-adrenergic agonists reduce adiponectin mRNA, secretion and plasma concentrations, with β
3-agonists having the greatest effect.179
Consistent with these findings, six months of treatment with rilmenidine, which reduces the firing rate of sympathetic neurons, increased adiponectin concentrations by approximately 35% in hypertensive human subjects, independently of changes in weight or visceral adiposity.180
In contrast, studies examining adiponectin concentrations in response to cold exposure-mediated activation of the sympathetic nervous system have been much less consistent: one study in humans suggests that cold exposure at 10°C decreases adiponectin concentrations after 90 minutes,101
while studies in rodents have reported increases,181
and no change183
in adiponectin mRNA or circulating concentrations in response to cold exposure (18–24 hours at 4–6°C). These discrepancies may reflect the different timepoints studied or species differences in responses to cold exposure.
Finally, a role for bone-derived hormones in the regulation of insulin sensitivity has been suggested by the recent observation that mice deficient in osteocalcin, a hormone secreted by osteoblasts, exhibit glucose intolerance and insulin resistance, likely due to reduced adiponectin concentrations.184
The influence of such osteogenic factors on glucose homeostasis is likely to be an active area of future research.
Together, these observations indicate that during periods of growth, stress, reproduction (and male sexual development), a number of endocrine systems may act to decrease circulating adiponectin concentrations, potentially increasing nutrient availability via a transient reduction in insulin sensitivity. Prolonged suppression of adiponectin production, however, as occurs in response to visceral adipocyte hypertrophy associated with weight gain, may prove maladaptive and lead to the development of insulin resistance and type 2 diabetes in susceptible individuals.