NPY Distribution

NPY has been found in every organ in the body; though, it is most abundant in the mammalian central and peripheral nervous system and the heart. In the central nervous system, in addition to the cerebral cortex and spinal cord, NPY immunoreactivity (NPY-ir) is particularly rich in the hypothalamic nuclei, namely: paraventricular, arcuate, suprachiasmatic, dorsal nucleus of vagus, and median eminence. In the sympathetic nervous system, NPY is co-localized with noradrenalin, and in the adrenal medulla, with epinephrine. Moreover, NPY has also been found in the respiratory tract, the biliary tract, the genitourinary system, the thyroid gland, immune, endothelial, and vascular smooth muscle cells, a subpopulation of parasympathetic neurons, and some species in platelets and megakaryocytes.

NPY’s Functions

Numerous physiological and pathological functions have been attributed to NPY. The most well known NPY actions are control of feeding behavior and energy metabolism. NPY is one of the most potent orexigenic peptides known. Its administration intracerebroventricularly causes a robust increase in carbohydrate-rich food intake in several species. Also via central actions, NPY has marked effect on peripheral metabolism, such as decrease of brown adipose tissue, thermogenesis, and increase of lipoprotein lipase activity that promotes white fat lipid storage. These observations suggest an important role of NPY in the pathophysiology of disorders such as obesity, anorexia nervosa, and diabetes. The role of NPY in reproduction, pregnancy, and onset of menarche, via modulating secretion of luteinizing hormone, has also been suggested. Acting centrally, NPY has been implicated in many neuro-physiological systems including but not limited to: facilitating learning and memory, shifting the circadian rhythm and the sleep-wake mechanisms, alteration of cardiorespiratory parameters, anxiolytic and anticonvulsive effects, neuronal growth and development, and decreasing alcohol intake. Recently, altered levels of NPY have been found in schizophrenia and Parkinson’s disease. Peripherally, NPY modulates immune

functions, gut motility and digestion, cirrhosis and ascites; and, exhibits important cardiovascular and angiogenic activities.

In the cardiovascular system, NPY has long been known as a vasoconstrictor of small arteries, leading to a stress-induced rise in blood pressure, either directly or indirectly, by enhancing the effect of catecholamines and other vasoconstrictors. Reciprocally, catecholamines have been shown to sensitize resistant vessels to NPY and augment NPY’s vasoconstrictive activity, A number of studies supported NPY’s role in stress-induced increase in blood pressure, including those that showed restoration of blood pressure during endotoxic and hemorrhagic shock, and exercise-induced rise in blood pressure in male human patients with angina pectoris. However, most recently, NPY has been shown to play a role in the regulation of basal vascular tone indirectly via modulation of the sympathetic system activity. In the latest study by Michalkiewicz et al., over-expressive rats had marked decrease, rather than increase, in both basal and stress-induced blood pressure, as well as lower levels of plasma catecholamines. In this case, NPY’s sympatholytic activity, through stimulation of the a 2-adrenergic receptors was postulated as the mechanism. Consequently, NPY has been implicated in both physiological and pathophysiological regulation of blood pressure, mechanisms of which, however, require further investigation.

Reference:

Movafagh, S. (2005). Neuropeptide Y receptor subtype (s) mediating migration, proliferation, and differentiation of endothelial cells in vitro, and angiogenesis in vivo.

The short bowel syndrome could be considered as a spectrum, where SBS patients with intestinal insufficiency are able to compensate for their malabsorption by increasing oral intake (hyperphagia) and adapt metabolically or pharmacologically, whereas SBS patients with intestinal failure (SBS-IF) require supplemental or total PS. It is clear that, although all patients with intestinal resections and malabsorption are included in the same syndrome, they are truly heterogeneous and present with many phenotypes as described in a recent review.

Although providing a lifesaving option in the home environment of the SBS-IF patient, these patients are not only challenged by the inconveniences and symptoms of their gastrointestinal disorder but also by the fear of – or the factual burden of – the potentially life-threatening complications of HPN. Therefore, treatments should seek to maximize remnant intestinal absorption, decrease malabsorption and accompanying symptoms, and reduce the fear, burdens, or complications related to HPN, thereby ultimately improving the health-related quality of life in SBS-IF patients.

In general, treatments aiming to increase intestinal absorption have consisted of dietary advice in conjunction with a limited pharmacological treatment armamentarium, mainly including antisecretory and antidiarrheal agents. Only few centers taking care of SBS patients have the facilities, methods, and resources to objectively assess effects of interventions on intestinal absorption in the individual patients. With the large interpatient treatment-effect variability in relation to interventions, mainly due to the large patient heterogeneity, the evaluations of the true effects of each of the components of the multidimensional treatment approach frequently rely on subjective global assessments by the physician and on the patients feedback rather than on objective measurements of intestinal function. In general, the maximal intestinal digestion and absorption is sought by maximizing the exposure of the mucosal surface area to nutrients, fluids, electrolytes, trace elements, and vitamins in the right form, concentration, and composition, at the right place, in the right environment, and in a timely fashion as described in a recent review.

Over the past decades, it has become increasingly clear that mucosal nerve ends and endocrine cells within the gastrointestinal tract mediate information via the enteric nervous system in response to the passing of luminal contents, thereby contributing to the highly coordinated processes of nutrient assimilation. These “neuroendocrine feedback mechanisms” often referred to as the “gastric, jejunal, ileal, or colonic brakes” may be disrupted by intestinal resections or mucosal disease. The attenuation of the meal-stimulated secretion of hormones, such as the glucagon-like peptides (GLPs) 1 and 2 and peptide YY by L cells in the terminal ileum and the colon, may be associated with some of the pathophysiological features of SBS patients with distal bowel resections: accelerated gastrointestinal motility, gastric and intestinal hypersecretion, diminished intestinal blood flow, disturbed immunological and barrier functions, and impaired mucosal replacement, repair, and adaptation. In SBS patients with a terminal ileum or colon in continuity, an increase in the endogenous hormonal secretion may be responsible for the progressive intestinal adaptation believed to occur in these patients.

Consequently, these observations have instigated the pharmacological use of hormonal factors in the intestinal rehabilitation of SBS patients. The first peptide hormone to gain marketing approval for the treatment of SBS patients is the GLP-2 agonist teduglutide. Teduglutide has recently gained approval by the US Food and Drug Administration and European Medicines Agency. NPS Pharmaceuticals has marketed teduglutide as Gattex® in the United States and seek to market teduglutide as Revestive®  in Europe in the near future. When introducing new therapies, it is prudent to evaluate and balance the benefit or clinical meaningfulness of interventions versus the inconveniences, adverse effects, risks, and costs. This chapter describes the results of the clinical trials of native GLP-2 and of teduglutide, leading to marketing approval of the latter for the treatment of SBS patients, in this respect.

Reference:

Palle Bekker Jeppesen