Systemic Fate of the Adipocyte-Derived Factor Adiponectin

Abstract

OBJECTIVEThe adipocyte-derived secretory protein adiponectin has been widely studied and shown to have potent insulin-sensitizing, antiapoptotic, and anti-inflammatory properties. While its biosynthesis is well understood, its fate, once in circulation, is less well established.RESEARCH DESIGN AND METHODSHere, we examine the half-life of adiponectin in circulation by tracking fluorescently labeled recombinant adiponectin in the circulation, following it to its final destination in the hepatocyte.RESULTSDespite its abundant presence in plasma, adiponectin is cleared rapidly with a half-life of ∼75 min. A more bioactive version carrying a mutation at cysteine 39 is cleared within minutes. Even though steady-state levels of adiponectin differ between male and female mice, we failed to detect any differences in clearance rates, suggesting that differences in plasma are mostly due to differential production rates. In a metabolically challenged state (high-fat diet exposure or in an ob/ob background), adiponectin levels are reduced in plasma and clearance is significantly prolonged, reflecting a dramatic drop in adiponectin production levels.CONCLUSIONSCombined, these results show a surprisingly rapid turnover of adiponectin with multiple fat pads contributing to the plasma levels of adiponectin and clearance mediated primarily by the liver. It is surprising that despite high-level production and rapid clearance, plasma levels of adiponectin remain remarkably constant.

The impact of obesity on secretion of adiponectin multimeric isoforms differs in visceral and subcutaneous adipose tissue

“…HMW isoform may also be, as the major active form, preferentially utilized by liver or other target organs. 16,37 The study presents limitations that should be acknowledged. Quantification of the adiponectin isoforms was performed using semiquantitative WB method.…”

“…Adiponectin profile might also be influenced beyond AT endothelium level. Although studies on mice suggest that adiponectin injected intravenously does not interconvert once in circulation, 35,36 more recently Scherer and co-workers 37 showed different clearance rates of plasma adiponectin isoforms in vivo, suggesting HMW as a storage compartment for lower subunits generated upon reduction of the HMW form. HMW isoform may also be, as the major active form, preferentially utilized by liver or other target organs.…”

Adiponectin and cardiovascular risk profile in patients with type 2 diabetes mellitus: parameters associated with adiponectin complex distribution

“…Of these, the most likely event is a decreased production of higher order complexes, since our recent results failed to identify clearance as a major determining factor for the different complexes. 8 In summary, we have analysed for the first time the distribution of all three major adiponectin complexes in plasma of a diabetic population. Previous methods employed were unable to resolve LMW and trimeric adiponectin.…”

Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth

“…The ADN protein is synthesized in adipose tissue and undergoes tightly regulated multimerization involving chaperone proteins, including disulfide-bond A oxidoreductaselike protein (DsbA-L), resulting in the assembly of oligomeric ADN proteins of different molecular weight (10). Multimerization into the high-molecular-weight (HMW) form increases the t 1/2 of ADN (11), and the insulin-sensitizing effect of ADN can largely be attributed to the HMW form (12). Low circulating levels of HMW ADN strongly predict the development of gestational diabetes mellitus (GDM) independent of maternal adiposity (13,14).…”