NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy

Abstract

Neuropeptide Y is the most potent physiological appetite transducer known. The NPY network is the conductor of the hypothalamic appetite regulating orchestra in the arcuate nucleus–paraventricular nucleus (ARC–PVN) of the hypothalamus. NPY and cohorts, AgrP, GABA and adrenergic transmitters, initiate appetitive drive directly through Y1, Y5, GABA^A and α₁ receptors, co-expressed in the magnocellular PVN (mPVN) and ARC neurons and by simultaneously repressing anorexigenic melanocortin signaling in the ARC–PVN axis. The circadian and ultradian rhythmicities in NPY secretion imprint the daily circadian and episodic feeding patterns. Although a number of afferent hormonal signals from the periphery can directly modulate NPYergic signaling, the reciprocal circadian and ultradian rhythmicities of anorexigenic leptin from adipocytes and orexigenic ghrelin from stomach, encode a corresponding pattern of NPY discharge for daily meal patterning. Subtle and progressive derangements produced by environmental and genetic factors in this exquisitely intricate temporal relationship between the two opposing humoral signals and the NPY network promote hyperphagia and abnormal rate of weight gain culminating in obesity and attendant metabolic disorders. Newer insights at cellular and molecular levels demonstrate that a breakdown of the integrated circuit due both to high and low abundance of NPY at target sites, underlies hyperphagia and increased adiposity. Consequently, interruption of NPYergic signaling at a single locus with NPY receptor antagonists may not be the most efficacious therapy to suppress hyperphagia and obesity. Central leptin gene therapy in rodents has been shown to subjugate, i.e. bring under homeostatic control, NPYergic signaling and suppress the age-related and dietary obesity for extended periods and thus shows promise as a newer treatment modality to curb the pandemic of obesity and metabolic syndrome.

Introduction

The appetite stimulating effects of neuropeptide Y (NPY) and related pancreatic polypeptides (PP) were demonstrated in 1984 (Clark et al., 1984; Kalra and Kalra, 2004b). Identification of the arcuate nucleus–paraventricular nucleus (ARC–PVN) axis as the effective pathway in the hypothalamus soon after ignited multidisciplinary research to decipher the operation of this axis in the management of daily meal patterning and eating disorders that range from anorexia on the one hand to relentless hyperphagia and excessive weight gain and obesity on the other (Bailer and Kaye, 2003; Gehlert, 1999; Kalra et al., 1996, Kalra et al., 1988a, Kalra et al., 1991b, Kalra et al., 1999; Kalra and Kalra, 1990, Kalra and Kalra, 2004c; Levens et al., 2004; Sahu et al., 1988b). The outcome of these endeavors is new insight into the neurochemical basis of energy homeostasis in the ARC–PVN axis, the backbone of the hypothalamic appetite regulating network (ARN).

The hypothalamic NPY network operates in diverse ways within the ARN to evoke appetite stimulating impulses in a timely manner (Kalra et al., 2003; Kalra and Kalra, 2004a, Kalra and Kalra, 2004c). A complex interacting dynamics of multiple neural and hormonal afferent signals participates on a moment-to-moment basis in the timely activation as well as cessation of NPY discharge in the ARC–PVN axis during the course of 24 h. In addition, the timely activation of NPY system entrained to the circadian clock resident in the hypothalamic suprachiasmatic nucleus (SCN), and disruptions of NPYergic signaling experimentally at various loci within the ARN, has established integrity of the NPY ARC–PVN axis as paramount for sustaining weight homeostasis (Dube et al., 1995, Dube et al., 1999; Jain et al., 1998; Kalra et al., 1998a, Kalra et al., 1998b, Kalra et al., 1999; Kalra, 1996; Pu et al., 2003; Sahu et al., 1988a). Consequently, the last two decades have witnessed a concerted effort aimed at designing selective NPY receptor antagonists (Gehlert, 1999; Levens et al., 2004) and gene transfer approaches (Kalra and Kalra, 2002, Kalra and Kalra, 2003) to subjugate NPYergic signaling on a long-term basis, and thereby suppress appetite and curtail the epidemic of obesity and metabolic syndrome. This new insight revealing the mandatory participation of NPY and cohorts in the etiology of eating disorders, obesity and attendant metabolic syndrome is summarized in this article.