A Tangled Threesome: Adiponectin, Insulin Sensitivity, and Adiposity

Can Mendelian Randomization Sort Out Causality?

  1. Jorge R. Kizer
  1. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
  2. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
  1. Corresponding author: Jorge R. Kizer, jorge.kizer{at}

The discovery nearly two decades ago that the adipocyte is more than a passive storehouse for lipids, that it is also an active secretory unit for peptides capable of system-wide regulation of energy metabolism, ushered in an exciting era of investigation into these newfound adipose-derived hormones (1). One intriguing object of these efforts has been the 244–amino acid protein adiponectin (2). Alone among major adipokines, adiponectin exhibits decreased rather than increased production with fat-mass expansion. Adiponectin is also the most abundantly secreted of all adipose-tissue peptides, and circulating levels correlate negatively with insulin resistance (IR), dyslipidemia, and inflammation (3). Such features have heightened interest in this molecule as a potential therapeutic target against the modern scourges of obesity and obesity-related disorders (2,3).

That adiponectin has insulin-sensitizing effects in mice is now well established (2). Available experimental data are most compelling for adiponectin’s actions on the liver, where it promotes fatty acid oxidation and suppresses gluconeogenesis, and on adipocytes, where it inhibits lipolysis (3). In addition, adiponectin has direct anti-inflammatory properties (1), further enabling salutary fat-mass expansion, which is deemed pivotal to its insulin-sensitizing effects (3).

Consistent with data in mice, prospective epidemiological studies have shown higher circulating adiponectin to be associated with lower risk of diabetes (4,5). Yet such observational data, susceptible as it is to confounding and reverse causation, cannot determine causality (6). In fact, observations from naturally occurring disorders of insulin action or from exogenous administration of insulin in humans have been cited to support the proposition that the direction of the association may be the reverse of that supposed (7). According to this hypothesis, the inverse association between adiponectin and IR may in fact reflect suppression of adiponectin production by hyperinsulinemia acting through spared, as yet undefined, signaling pathways (7). Hence, …

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