Anorexigenic neuropeptides as anti-obesity and neuroprotective agents: exploring the neuroprotective effects of anorexigenic neuropeptides

Abstract

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

Keywords: Alzheimer´s-like pathology; anorexigenic neuropeptides; antiobesity treatment; neuroprotection.

Figure 1. Scheme of peptides involved in food intake regulation

Food intake regulating peptides are produced in the periphery, as well as in the brain. The main regulators of energy homeostasis are anorexigenic (food intake lowering) leptin, produced by white adipose tissue, and orexigenic (food intake stimulating) ghrelin, produced by the stomach. Many other anorexigenic hormones are produced in the gastrointestinal tract, for example, amylin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), or peptide YY (PYY). To induce biological effects, these peptides must penetrate to the brain; either through nervus vagus to the nucleus of the solitary tract (NTS) or through the blood–brain barrier (BBB) to the hypothalamus that is the main center of food intake regulation. In the arcuate nucleus (ARC), located at the base of the third ventricle (3V) adjacent to the media eminence (ME), two distinct populations of neurons regulate food intake with antagonistic effects: anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) peptide, alongside orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP). These neuronal populations project to other hypothalamic nuclei, such as ventromedial nucleus (VMN), dorsomedial nucleus (DMN), lateral hypothalamic area (LHA), and paraventricular nucleus (PVN), where are expressed other anorexigenic (corticotropin-releasing hormone [CRH], neuropeptide FF [NPFF], pituitary adenylate cyclase-activating peptide [PACAP], prolactin-releasing peptide [PrRP], and thyrotropin-releasing hormone [TRH]) or orexigenic neuropeptides (galanin, melanin-concentrating hormone [MCH], orexins).

Figure 2. Scheme of beneficial effects of anorexigenic neuropeptides or their modified analogs in the treatment of obesity and neurodegeneration

Administration of anorexigenic neuropeptides or their modified analogs reduces food intake, resulting in weight loss and decreased white adipose tissue, known for pro-inflammatory cytokine secretion. This treatment further mitigates neuroinflammation, characterized by microgliosis, and astrocytosis, lowers levels of amyloid-β (Aβ), and diminishes neurofibrillary tangles formed by hyperphosphorylated Tau protein in the brain. Additionally, it promotes synaptogenesis and neurogenesis, leading to improved learning and memory. BBB: blood brain barrier.