New Pharmacological Perspectives for the Leptin Receptor in the Treatment of Obesity

Abstract

After its discovery in 1994, leptin became the great hope as an anti-obesity treatment based on its ability to reduce food intake and increase energy expenditure. However, treating obese people with exogenous leptin was unsuccessful in most cases since most of them present already high circulating leptin levels to which they do not respond anymore defining the so-called state of "leptin resistance." Indeed, leptin therapy is unsuccessful to lower body weight in commonly obese people but effective in people with rare single gene mutations of the leptin gene. Consequently, treatment of obese people with leptin was given less attention and the focus of obesity research shifted toward the prevention and reversal of the state of leptin resistance. Many of these new promising approaches aim to restore or sensitize the impaired function of the leptin receptor by pharmacological means. The current review will focus on the different emerging therapeutic strategies in obesity research that are related to leptin and its receptor.

Combinatorial gene construct and non-viral delivery for anti-obesity in diet-induced obese mice

“…eventually discontinued due to potential safety issues, such as harmful immune reactions [10,35]. As a workable alternative to the peptidergic therapy, there have been a large number of attempts to manage obesity using anti-obesity gene delivery.…”

Leptin resistance in obesity: An epigenetic landscape

“…Although the effects were minimal and it appears that leptin replacement is not sufficient by itself, these results suggest that a multitherapy of leptin in combination with other molecules with known physiological roles in the regulation of body weight may be able to target several mechanisms related to obesity at the same time to reduce compensation to leptin treatment. In this sense, a combination of leptin with leptin-sensitizing molecules is a promising pharmacological approach for weight loss [22]. For example, amylin and leptin, triinfusion of cholecystokinin, leptin and amylin and glucagon-like peptide 1 and leptin therapies result in greater inhibition of food intake and body weight loss than leptin monotherapy [23][24][25][26][27].…”

Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

“…Prevention and/or reversal of leptin resistance constitute a major challenge in obesity research. Understanding the precise molecular basis for leptin resistance must help to design efficient therapeutic strategies to restore leptin sensitivity [46]. Several mechanisms have been identified to trigger central leptin resistance.…”