Restoring leptin sensitivity in metabolic and extra-metabolic leptin resistance: Pharmacologic strategies, systemic implications, and future directions.

The presence of leptin resistance is a key barrier to the successful management of obesity. The most recent study has focused on pharmacological drugs that are associated with inflammation and endoplasmic reticulum stress, as well as inhibitors of negative regulators, including PTP1B, SOCS3, and HDAC6, and substances that affect the mTOR and cAMP/Epac/Rap1 signaling pathways. Having an understanding that leptin resistance is caused by defective leptin signaling pathways, such as a disruption in the JAK-STAT pathway or an increase in the expression of SOCS3, shows the difficulty of restoring sensitivity. The physiological implications of leptin resistance extend beyond the regulation of metabolism and can influence the cardiovascular system, the liver (NAFLD/MASLD), the immunological system, the inflammatory system, reproductive health and the neuroendocrine system. The fact that leptin has metabolic impacts on various systems highlights the importance of taking an integrated strategy to treatment procedures. Within the context of metabolic and extra-metabolic leptin resistance, this review provides a summary of recent literature evidence pertaining to the restoration of leptin responsiveness. Also, we include a discussion regarding pharmacologic strategies, systemic implications, and future directions. See also the graphical abstract(Fig. 1).