Adiponectin isoforms (2. Factors regulating HMW Adiponectin formation, secretion and levels)

HMW adiponectin and TZD

Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism ^Ref . The addition of pioglitazone (1–3 micromm) in vitro increased the secretion of the HMW isoform, with no significant effect on the other isoforms. Human adipose tissue was also examined for changes in adiponectin mRNA levels upon pioglitazone treatment. No difference was detected, suggesting that the effect of pioglitazone is not at the transcriptio- nal level but, rather, at a posttranscriptional phase of the secretory pathway. Additional experiments were conducted to determine whether adiponectin expression was mechanistically similar in other adipose cells. Examination of primary human adipocytes revealed an increase in intracellular HMW isoform with a decline in LMW forms following pioglitazone treatment, with a corresponding increase in the secreted HMW form. Similar results were observed with primary mouse adipocytes, 3T3-F422A cells, and SGBS human adipocyte cells, although differences in the distribution of HMW and LMW isoforms were apparent between cell types. Although there are differences in isoforms between species, in all cases pioglitazone served to increase the secretion of the HMW form of adiponectin ^Ref .

HMW adiponectin and clozapine

The effects of olanzapine on adiponectin protein expression and secretion in in vitro-differentiated primary human adipocytes were also examined. Patients receiving olanzapine had significantly lower total serum adiponectin as compared with those on conventional treatment and controls (5.23 +/- 1.53 ng/mL vs. 8.20 +/- 3.77 ng/mL and 8.78 +/- 3.8 ng/mL; p < 0.05 and p < 0.01, respectively). The HMW adiponectin was also reduced in patients on olanzapine as compared with the disease and healthy control groups (1.67 +/- 0.96 ng/mL vs. 3.87 +/- 2.69 ng/mL and 4.07 +/- 3.2 ng/mL; p < 0.05 for both). The LMW adiponectin was not different between patient groups (p = 0.15) but lower in patients on olanzapine as compared with controls (3.56 +/- 0.85 ng/mL vs. 4.70 +/- 1.4 ng/mL; p < 0.05). in vitro, short durati- on (up to 7 days) olanzapine exposure had no effect on total adiponectin expression or multimer composition of secreted protein ^Ref .

HMW adiponectin an the lack of functional insulin receptors

Paradoxical hyperadiponec­tinemia in patients with severe insulin resistance due to genetically defective insulin receptors was reported. This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12–54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3–54.2] vs. 8.9 mg/l [1.5–28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. Hyperadiponec­tinemia resolved in parallel with reduction of insulin receptor antibodies and clinical resolution of insulin resistance. Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated ^Ref .