Neuropeptide Y Deficiency Attenuates Responses to Fasting and High-Fat Diet in Obesity-Prone Mice

Abstract

Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice. Diabetes 55:3091-3098, 2006 E nergy balance involves a complex interaction between hormones, such as leptin, insulin, and glucocorticoids, and key neurons in the hypothalamus, brainstem, and other areas of the central nervous system (1). Neuropeptide Y (NPY) is expressed in the hypothalamus, stimulates food intake, decreases energy expenditure, and increases body weight when administered in the brain (1). Consistent with its role as an orexigenic peptide, hypothalamic NPY expression is increased during fasting and hypoglycemia and suppressed by feeding, leptin, and insulin (1). Despite the strong pharmacological evidence supporting its role in energy balance, genetic disruption of NPY did not affect feeding or body weight in mice bred on a mixed 129J-C57Bl/6J background (2). Paradoxically, deletion of NPY or the Y1 and Y5 receptors that mediate effects of NPY on energy balance resulted in mild obesity (3-6). Nonetheless, loss of NPY attenuated hyperphagia and obesity in Lep ob/ob mice (7). Others have also shown that NPY deficiency decreases hyperphagia after fasting and hypoglycemia (8 -10). Furthermore, deletion of NPY Y2/Y4 receptors prevents diet-induced obesity (DIO) (11).We reasoned that the controversies surrounding the actions of NPY in these genetic models are partly due to the use of the 129 mouse strain, which is resistant to obesity (12). The seemingly normal phenotype of NPYdeficient mice could also result from compensatory developmental changes. For example, ablation of hypothalamic neurons expressing NPY/AGRP did not alter feeding in neonatal mice, whereas ablation in adults caused starvation (13,14). AGRP is coexpressed with NPY in the arcuate nucleus, and both peptides ...

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…Experimental procedures were in accordance to institutional guidelines and regulations. Male C57BL/6J wild-type and npyϪ/Ϫ mice (Patel et al, 2006;Qi et al, 2006), were housed n ϭ 5 per cage in 12 h light/dark cycle (lights on 7:00 A.M.) and ambient temperature 22°C. Chow and water were provided ad libitum.…”

“…A previous study has shown that infusion of NPY intracerebroventricularly impairs insulin sensitivity and increases endogenous glucose production (Marks and Waite, 1997;van den Hoek et al, 2004). We administered resistin intracerebroventricularly in NPY deficient C57BL/6J mice (npyϪ/Ϫ) (Patel et al, 2006) and performed a hyperinsulinemic-euglycemic clamp and tracer kinetics. Resistin treatment did not change basal or clamp chemistries (Table 3).…”

Dietary fat alters the response of hypothalamic neuropeptide Y to subsequent energy intake in broiler chickens

“…Administration of NPY to the paraventricular nucleus (PVH) increases the activity of PVH neurons by presynaptically inhibiting local γ-amino butyric acid release (Cowley et al, 1999) and decreases brown adipose tissue thermogenesis (Egawa et al, 1991). NPY knockout mice have increased energy expenditure (increased O 2 consumption), increased uncoupling protein-1 (UCP-1) in brown adipose tissue and increased cold-evoked thermogenesis in white adipose tissue and are less susceptible to diet-induced obesity (Patel et al, 2006;Chao et al, 2011). In the present study, chickens fed the HF diet for 35 days to induce obesity (fat) were compared with chickens fed the LF diet for 35 days (lean).…”

“…NPY reduces energy expenditure by decreasing adipose tissue thermogenesis (Egawa et al, 1991;Patel et al, 2006;Chao et al, 2011;Zhang et al, 2014). The obesity of ob/ob mice is attenuated when NPY is knocked out (Erickson et al, 1996;Segal-Lieberman et al, 2003).…”

“…The obesity of ob/ob mice is attenuated when NPY is knocked out (Erickson et al, 1996;Segal-Lieberman et al, 2003). NPY deficiency attenuates responses to a palatable high fat diet in mice (Hollopeter et al, 1998;Patel et al, 2006). Animals in which POMC neurons have been knocked out are obese and hyperphagic (Butler and Cone, 2002;Mencarelli et al, 2012;Diané et al, 2014;Raffan et al, 2016).…”