Adiponectin: More Than Just Another Fat Cell Hormone

The view of the adipocyte as simply a storage depot for fat is no longer tenable. Among the various “adipocytokines,” adiponectin, which is an abundant circulating protein synthesized solely in adipose tissue, appears to play a very important role in carbohydrate and lipid metabolism and vascular biology. Adiponectin appears to be a major modulator of insulin action and its levels are reduced in type 2 diabetes, which could contribute to peripheral insulin resistance in this condition. It has significant insulin-sensitizing as well as anti-inflammatory properties that include suppression of macrophage phagocytosis and TNF-α secretion and blockage of monocyte adhesion to endothelial cells in vitro. To date, however, adiponectin’s putative antiatherogenic potential in humans remains substantially weaker and less well studied than its insulin-sensitizing effects.

Although further investigations are required, adiponectin administration, as well as regulation of the pathways controlling its production, represents a promising target for managing obesity, hyperlipidemia, insulin resistance, type 2 diabetes, and vascular inflammation.

Numerous important questions about adiponectin await further study. The mechanisms by which adiponectin is synthesized and secreted need to be elucidated, as do the signals that reduce adiponectin expression in adipocytes with increasing adiposity. Similarly, the role and regulation of adiponectin oligomerization need to be defined. The molecular mechanisms by which adiponectin exerts its multiple functions and whether its actions are receptor mediated still remain a mystery. Is the primary activity of adiponectin antiatherosclerotic, or is it principally a modulator of lipid metabolism and regulator of insulin sensitivity—or is it all of the above? The answers to these and other intriguing questions will undoubtedly provide additional insight into the metabolic roles of this new adipocyte hormone.

The domain structure of Acrp30: signal sequence, species-specific variable region, collagenous domain, and globular trimerization domain. Modified with permission from Berg et al. (23).

Model for assembly of adiponectin complexes. Three monomers form a trimer through associations between their globular domains. Four to six trimers associate noncovalently through their collagenous domains to form high-molecular-weight oligomers, which circulate in the plasma. Modified with permission from Berg et al. (23).

Hypothetical model for the actions of adiponectin. In skeletal muscle, adiponectin increases tyrosine phosphorylation of the insulin receptor. This effect may contribute to increased insulin sensitivity. It also increases fatty acid oxidation, probably by activation of 5′-AMP kinase, with resultant decreased intramyocellular steatosis. In the liver, the decreased free fatty acid influx and increased fatty acid oxidation contribute to reduced hepatic glucose output and VLDL triglyceride synthesis. In vascular endothelium, adiponectin decreases monocyte adhesion to endothelium, suppresses macrophage-to-foam cell transformation, and inhibits vascular smooth muscle cell proliferation and migration.

Source: 

1. Manju Chandran, MD1,
2. Susan A. Phillips, MD2,
3. Theodore Ciaraldi, PHD1 and
4. Robert R. Henry, MD1

-Author Affiliations

1. ¹Division of Diabetes, Endocrinology and Metabolism, University of California, San Diego School of Medicine
2. ²Division of Pediatric Endocrinology, University of California, San Diego School of Medicine, and VA San Diego Health Care System, San Diego, California

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