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May 3, 2016: Leptin resistance is a challenging topic of conversation in obesity. It is defined by a state in which the body does not display any adapted response to high endogenous or exogenous levels of leptin while continuing to maintain excess body weight¹. This may be due to a decreased uptake of leptin in the brain, reduced central response to leptin, or hypothalamic inflammation¹. Congenital leptin deficiency is a rare cause of extreme obesity characterized by high levels of circulating leptin, early-onset of obesity, hyperphagia, and other hormonal and metabolic disturbances². If not properly diagnosed, it can sometimes be misdiagnosed as leptin resistance^1,2. Investigators are making a difference in the study of early onset extreme diabetes by exploring the significance of bioactive leptin in obesity research.

Dr. Wabitsch and his team at the University of Ulm in Germany performed in-vivo studies in leptin deficient obese mice. Mice were administered a mutant version of leptin (D100Y) that is not functional. When compared to the control mice that were administered the non-mutant version of leptin, it was found that the mutant form of leptin proved to be ineffective in decreasing food intake and body weight even when dosage was increased 3 times over the course of time². This was clearly unlike the control mice that showed a marked decrease in food intake and body weight². This research illustrates how single amino acid mutations (Aspartic acid → Tyrosine at position 100 in this case) can display normal levels of circulating leptin while also displaying symptoms of hyperphagia and increased body weight. At the same time, Dr. Wabitsch’s findings open up the discussion on whether simply measuring levels of total leptin in circulation can provide a clearer picture of the underlying cause of metabolic defects. Current ELISAs on the market are only capable of measuring total leptin levels in circulation. However, an individual’s leptin levels may be normal even if they exhibit symptoms of metabolic distress and extreme obesity. Instances such as this can result in a diagnosis of other hormonal defects that may not actually be present. By only measuring bioactive leptin, investigators can rule out other causes of extreme obesity, both behavioral and biological. This therefore demonstrates the significance of bioactive leptin in obesity research.

1. Balland & Cowley. (2015). New insights in leptin resistance mechanisms in mice. Frontiers in Neuroendocrinology, 39, 59-65.
2. Wabitsch et al. (2015). Biologically inactive leptin and early-onset extreme obesity. N Engl J Med, 372, 48-54.