Natural Products From Plants Targeting Leptin Resistance for the Future Development of Anti‐Obesity Agents

ABSTRACT Obesity is a serious health threat, which has affected 16% of adults globally in 2022 and shows a trend toward youthfulness. Leptin, as a regulator of body weight, can suppress appetite and promote energy expenditure, making it potential in obesity treatment. Nevertheless, with the progress of relevant research, it is worth noting that monotherapy with leptin is not an effective strategy since most obese individuals are hyperleptinemic and resistant to leptin, where high levels of leptin fail to exert its weight‐loss effects. Therefore, the potential to unlock the weight‐loss properties of leptin using pharmacology to improve resistance has provided a new direction for this field. However, most synthetic medicines have retreated from the market due to their undesirable side effects, while natural products are increasingly sought after for drug development due to their minimal side effects. Indeed, natural products are ideal alternatives to oral synthetic agents since a growing body of research has demonstrated their desirable effects on improving leptin resistance through potential therapeutic targets like the JAK2/STAT3 signaling pathway, protein tyrosine phosphatase 1B, the exchange proteins directly activated by cAMP/Ras‐related protein 1 signaling pathway, endoplasmic reticulum stress, pro‐opiomelanocortin gene, and leptin levels. This review outlines natural products that can improve leptin resistance by inhibiting or activating these targets and evaluates their efficacy in experiments and human clinical trials, offering insights for the development of anti‐obesity agents. However, more high‐quality clinical research is necessary to validate these findings, as current clinical evidence is constrained by heterogeneity and small sample sizes.