Table 3.

Mechanisms involved in GLP-1 RA-associated appetite and weight reduction as reported in a recently published comprehensive study focusing on the effects of semaglutide (compared to liraglutide) on diet-induced obesity in mice (based on Secher et al., 2014 and [72] and Gabery et al., 2020 [73]).

Aspects of the mechanism of GLP-1 RA-induced weight loss	Findings	Explanation/commentary
Access of peripherally circulating GLP-1 RAs into the central nervous system	•No transport across the blood–brain barrier (BBB) •Uptake of liraglutide and semaglutide into selected brain areas: (a) not protected by the BBB (circumventricular organs); (b) protected by the BBB: for example, nucleus arcuatus (hypothalamus), area postrema, nucleus tractus solitarii, and dorsal motor nucleus of the vagus nerve (brain stem) •A potential role of tanycytes in mediating uptake of semaglutide into some brain areas	•Absence of GLP-1 Rs in brain endothelial cells •Uptake of liraglutide and semaglutide into selected brain areas is similar, but not fully identical (e.g., semaglutide had a distribution extending more laterally and into posterior portions of the nucleus arcuatus)
Access of GLP-1 RAs to GLP-1 receptors in the brain	•Brain areas with a high uptake of semaglutide are equipped with GLP-1 receptors (mainly in the hypothalamus and hindbrain)	•Uptake of fluorescently labeled semaglutide is substantially reduced in GLP-1 R−/- animals
Direct effects of GLP-1 RAs on the hypothalamus (nucleus arcuatus)	•POMC/CART neurons are depolarized (stimulated); NPY/AgRP neurons are hyperpolarized (inhibited)	•As previously shown for liraglutide
Neuronal activation in brain areas accessible for GLP-1 RAs	•C-Fos activation observed in the area postrema and nucleus tractus solitarii (brain stem)	•Immediate consequence of GLP-1 R engagement
Neuronal activation in brain areas not directly accessible for GLP-1 RAs (“secondary activation”)	•C-Fos activation in the bed nuclei of the stria terminalis, central amygdala nucleus, midline group of the dorsal thalamus, parasubthalamic nucleus, and parabrachial nucleus (CGRP-expressing neurons)	•These are brain regions that have been identified as part of an appetite-regulation pathway related to meal termination [74]
Food intake and body weight	•Reduced (strong initial effect and some attenuation over time); substantial weight reduction compared to placebo treatment	•Reduced caloric intake is the main mechanism leading to weight loss with GLP-1 RAs
Food preference	•Semaglutide reduced intake of chocolate bars in favor of chow	•These results suggest that GLP-1 RAs may promote healthier food choices
Energy expenditure	•Weight loss induced by caloric restriction leads to a compensatory reduction in energy expenditure •Weight loss induced by semaglutide only transiently did so: energy expenditure returned to baseline levels within a week	•Interferes with an effective compensatory mechanism counteracting weight loss; needs to be confirmed in human studies

BBB: blood–brain barrier, GLP-1 R: glucagon-like peptide-1 receptor, GLP-1 RA: GLP-1 receptor agonist, POMC/CART: proopiomelanocortin/cocaine- and amphetamine-regulated transcript, NPY/AgRP: neuropeptide Y/agouti-related peptide.