You Are What You Secrete is a summary and editorial by Saltiel in which he discusses two articles concerning adiponectin.¹  Saltiel emphasizes that our notion of the adipocyte as merely a cargo space for fat has undergone a dramatic change.  We now know that adipose tissue is much more complex than previously thought, secreting proteins which include tumor necrosis factor (TNF)-a, leptin, adipsin, resistin and adiponectin known also as Acrp30 or adipoQ.  These proteins perform diverse functions but share structural properties of cytokines, and are referred to collectively as “adipokines”.  Dynamic interactions occur between these proteins and dictate the extent to which insulin is sensed in its target tissues. In an article referred to by Saltiel, Berg et al² report that a single injection of adiponectin leads to a 2-3 fold elevation in its circulating levels, which precipitates a transient decrease in basal glucose levels.  Similar treatment in ob/ob or streptozotocin - treated mice transiently abolishes hyperglycemia.  This relative hypoglycemic effect is not associated with an increase in insulin levels.  Moreover, in isolated hepatocytes adiponectin increases the ability of sub-physiological levels of insulin to suppress glucose production.  Berg et al propose that adiponectin is a potent insulin enhancer linking adipose tissue and whole body glucose metabolism. 

In the article by Yamauchi et al the reversal by adiponectin of insulin resistance associated with both lipoatrophy and obesity is described. Yamauchi et al³ discuss the findings that recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes to chromosome 3q27, where the gene encoding adiponectin is located.  This group demonstrated decreased expression of adiponectin and its correlation with insulin resistance in mice models of altered insulin sensitivity.  Adiponectin decreases insulin resistance in obese mice by decreasing triglyceride content in muscle and liver.  Insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either given alone.  Yamauchi et al concluded that decreased adiponectin production is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy.  Their data also indicate that administration of adiponectin might provide a novel treatment modality for insulin resistance in type 2 diabetes.

Editorial Comment: Adiponectin is a 247 amino acid protein whose expression in adipose tissue is depressed in obese animals.  The plasma concentrations are low in these obese animals and also in obese humans, which is a pattern directly opposite to those of leptin, another adipocyte hormone.  As discussed by Yamauchi et al, mice ingesting a high fat diet with increased fat accumulation had low tissue levels of adiponectin mRNA and low serum concentrations.  Insulin resistance as reflected by hyperglycemia and hyperinsulinemia occurred. 

Administration of rosiglitazone, an inhibitor of peroxisome proliferator-activated receptor-g which is an essential element for adipogenesis, increased adiponectin tissue mRNA values and also serum levels.  Serum glucose was decreased as were serum levels of insulin. 

In other mouse models of obesity (e.g. leptin receptor deficiency), administration of adiponectin lowered blood glucose and insulin values.  In another mouse model, a lipodystrophic mouse without fat, serum concentrations of adiponectin were undetectable.  Hyperglycemia and hyperinsulinemia were present.  Administration of adiponectin lowered serum glucose and insulin levels.  Both leptin and adiponectin were required in the lipoatrophic mice to restore serum glucose and insulin values to normal.

In the article by Berg et al, serum glucose concentrations were decreased with the administration of recombinant adiponectin to wild type, leptin deficient, and insulin deficient mice.  Berg et al also demonstrated that adiponectin depressed hepatic glucose output in vitro which is thus the second physiological effect that might contribute to enhanced insulin sensitivity.  In calorically restricted wild type mice, serum adiponectin concentrations were twice those of freely feeding animals suggesting that this adipokine may be important in prolonging the lives of such animals.

Thus, the data in these manuscripts indicate that adiponectin plays a key role in energy metabolism.  It enhances insulin sensitivity by lowering serum and tissue triglyceride values, by uncoupling of oxidative phosphorylation in muscle, and by suppressing hepatic glucose output.  In addition to the effects on energy metabolism, adiponectin depresses the inflammatory response that accompanies atherogenesis.  Indeed, patients with coronary artery disease have lower plasma adiponectin concentrations than do controls.  Adiponectin inhibits inflammation in part by suppressing proliferation of myelomonocytic progenitor cells by accelerating apoptosis.  The potential utilization of adiponectin as a therapeutic agent for patients with obesity, diabetes mellitus types 1 and 2, hyperlipidemia, and/or atherogenic disorders is clearly enormous. A lead article regarding Adipose Tissue as an Endocrine Gland will appear soon in GGH.

Allen Root, MD

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