Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

Figure 3 The hedonic and homeostatic controls of energy balance. Peripheral signals from the Liver, adipose tissue pancreas, GI-tract cross the BBB to directly signal to neurons of the ARC of the hypothalamus. GI-tract enteroendocrine hormones and chemo- and mechanoreceptor neural afferents can also indirectly activate the ARC via the vagus nerve and brainstem. The net output of the ARC neurons is relayed to second order intrahypothalmic neurons in the PVN, and LHA that express the MC4R. GLP-1Rs have been localized pre-clinically in the ARC and PVN[50,51], stimulation of theses receptors inducing reductions in food intake and weight loss potentially through efferent pathways that involve the activation of TRH and CRH expressing neurons and pre-ganglionic sympathetic and parasympathetic neurons. Feeding and meal termination are also influenced by hedonic, reward-related factors centrally processed in the VTA. Though the interactions between peripheral nutrient signals and rewards neurocircuitry are not extensively defined (grey dashed arrows) GLP-1Rs have been localized pre-clinically in the VTA[52]. Previously considered as separate entities, severe cross-interactions exist between central homeostatic and hedonic control centres[53]. This communication may be mediated by central GLP-1 signalling[36,37,54]. GI-tract: Gastrointestinal tract; BBB: Blood-brain barrier; ARC: Arcuate nucleus; PVN: Paraventricular nucleus; LHA: Lateral hypothalamic area; MC4R: Melanocortin 4 receptor; TRH: Thyrotrophin releasing hormone; CRH: Corticotrophin releasing hormone; VTA: Ventral tegmental area; PP: Pancreatic polypeptide; CKK: Cholecystokinin; PYY: Polypeptide-YY; OXM: Oxymodulin.