Review articleNew insights in leptin resistance mechanisms in mice

- Leptin enters the brain via a specific transport across tanycytes of the median eminence. This transport can be pharmacologically rescued in DIO mice.
- Increased expression of SOCS3, PTP1B, PTPCT and SHIP2 in DIO is involved in cellular leptin resistance.
- Hypothalamic gliosis is associated with obesity in humans and rodents and alters neuronal circuits.
- DIO mice still display a cellular and physiological response to endogenous leptin.
- Leptin sensitivity can be rescued in DIO mice, hypothalamic alterations of obesity are reversible.

Leptin resistance is one of the main challenges of obesity. To date, two levels of resistance have been identified, first a decreased rate of leptin uptake into the brain and secondly a diminished central response to leptin. New findings have identified the mechanisms of leptin transport and demonstrated that it can be rescued in obesity, but it did not overcome the problem of central resistance. Alteration in the actions of leptin following diet-induced obesity (DIO) appears to be a multifactorial condition. Several phosphatases are inhibiting leptin signaling pathways in a pathological way. Besides, hypothalamic inflammation alters the neuronal circuits that control metabolism. Recent studies describing both mechanisms (inhibition of leptin signaling and inflammation), have provided key insights to potential new targets for treatment. However, recent data showing that DIO mice may conserve a cellular and physiological response to endogenous leptin, highlights the need to redefine the concept of “leptin resistance”.