Abstract by Jonas Odgaard Petersen

Obesity is a chronic disease that affects more than 650 million people globally. In addition to directly contributing to reduced quality of life, the accumulation of excess fat mass is a major risk factor for type 2 diabetes, cardiovascular diseases and cancer, and thus solving the obesity crisis has become one of the most critical health challenges of modern times. Currently available pharmacotherapies are incapable of correcting the underlying disease mechanism of obesity, that drive rapid weight regain upon treatment cessation. Consequently, there is an unmet need for the development of new efficacious anti-obesity pharmacotherapies. Emerging insights into the molecular origins of appetite regulation suggest that coordinated targeting of multiple biological pathways is likely needed to persistently lower body weight beyond 20%. The overall aim of this thesis was to evaluate the therapeutic utility of selectively targeting ion-channel modulators to brain regions governing appetite regulation as a novel strategy for obesity treatment. For this, two distinct therapeutic concepts were developed based on targeting the nicotinic acetylcholine receptors (nAChR) and the N-methyl-D-aspartate receptors (NMDAR).

In the first project, we investigated the hypothesis that glucagon-like peptide 1 (GLP-1) can be utilized to selectively deliver nAChR agonists to feeding regions. Two distinct molecular strategies were devised based on cleavable and non-cleavable linkers, and the conjugates were pharmacologically evaluated in vitro and in vivo. We demonstrate that targeting of nAChR agonists amplifies the weight loss efficacy of GLP-1 in preclinical models of obesity while mitigating hallmark adverse effects pertaining to non-specific nAChR agonism.

In the second project, we explored pharmacological NMDAR antagonism in the context of obesity treatment. We demonstrate that the NMDAR antagonist MK-801 alone lowers body weight but that its therapeutic utility is limited by intolerable adverse effects on locomotion and body temperature. To unleash the therapeutic utility of MK-801, we devised conjugates capitalizing on GLP-1 to restrict MK-801 actions to neural feeding regions. Conjugation of MK-801 to GLP-1 through a reducible disulfide linker led to synergistic weight loss efficacy compared to the monotherapies, while being devoid of hallmark adverse effects pertaining to MK-801. We demonstrate that the efficacy of this therapeutic concept rivals the currently best anti-obesity pharmacotherapy, semaglutide, in preclinical models of diet-induced and genetic obesity. Finally, we provide mechanistic evidence suggesting that the superior weight loss is driven by modulation of glutamatergic synaptic plasticity in the hypothalamus.