Challenges and opportunities of defining clinical leptin resistance

Abstract

The widespread use of the inadequately defined term "leptin resistance" led the National Institutes of Health to convene a workshop aimed at developing a quantitative definition of this term that would facilitate mechanistic research into leptin's actions in human health and disease. Although leptin-responsive conditions are recognized, the field is limited by a lack of robust, easily quantifiable behavioral or metabolic biomarkers of the hormone's action. Further advances require biomarkers that can be used to identify patients who may benefit from leptin therapy and that are useful for understanding the determinants of clinical leptin responsiveness.

Figure 1

Number of publications per year citing “leptin resistance” since the hormone's discovery. Data from PubMed.

Figure 2

Potential sites/mechanisms interfering with the regulation of energy balance to produce obesity. Leptin is transported across the blood brain barrier (BBB) to access first order, LEPR-B expressing neurons, which connect with downstream neurons to eventually modulate food intake and energy expenditure. Other circuits, including those not modulated by leptin, also contribute to the control of feeding and energy expenditure. Interference (red) with any of these processes, including BBB transport of leptin, cellular processes in LEPR-B neurons (such as LEPR-B signaling), or alterations in the neural function, “wiring”, or plasticity in any of the leptin-regulated or leptin-independent circuits that contribute to energy balance are expected to promote obesity (and increase circulating leptin concentrations).