Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

Abstract

Neuropeptide Y is implicated in energy homeostasis, and contributes to obesity when hypothalamic levels remain chronically elevated. To investigate the specific role of hypothalamic Y2 receptors in this process, we used a conditional Y2 knockout model, using the Cre-lox system and adenoviral delivery of Cre-recombinase. Hypothalamus-specific Y2-deleted mice showed a significant decrease in body weight and a significant increase in food intake that was associated with increased mRNA levels for the orexigenic NPY and AgRP, as well as the anorexic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) in the arcuate nucleus. These hypothalamic changes persisted until at least 34 days after Y2 deletion, yet the effect on body weight and food intake subsided within this time. Plasma concentrations of pancreatic polypeptide and corticosterone were 3-to 5-fold increased in hypothalamus-specific Y2 knockout mice. Germ-line Y2 receptor knockout also produced a significant increase in plasma levels of pancreatic polypeptide. However, these mice differed from conditional knockout mice in that they showed a sustained reduction in body weight and adiposity associated with increased NPY and AgRP but decreased POMC and CART mRNA levels in the arcuate nucleus. The transience of the observed effects on food intake and body weight in the hypothalamus-specific Y2 knockout mice, and the difference of this model from germ-line Y2 knockout mice, underline the importance of conditional models of gene deletion, because developmental, secondary, or extrahypothalamic mechanisms may mask such effects in germ-line knockouts.neuropeptide Y ͉ pancreatic polypeptide ͉ cre-lox ͉ arcuate nucleus N europeptide Y (NPY) in the hypothalamus is known to be a strong stimulus for food intake (1, 2), and induces many neuroendocrine and metabolic changes that favor energy storage. Such changes include decreased thermogenesis in brown adipose tissue, hyperinsulinemia, hypercorticosteronemia, and insulin hyperresponsiveness in white adipose tissue (3, 4). All of these neuroendocrine and metabolic effects of central NPY administration persist even when NPY-induced hyperphagia is prevented by pair-feeding (3, 4), demonstrating that hyperphagia is not the only mechanism by which central NPY increases adiposity.Although numerous other hormones and peptides act within the hypothalamus to regulate energy homeostasis, many exert an important component of their effects via actions on the hypothalamic NPY-ergic system (5-7), demonstrating the pivotal role of NPY in coordinating energy homeostasis. However, it is not clear which of the 5 cloned Y-receptors (Y1, Y2, Y4, Y5, and y6) are responsible for these effects (8).There is increasing evidence that Y2 receptors are involved in energy homeostasis. Over 80% of NPY-containing neurons in the arcuate nucleus (Arc) coexpress Y2 receptor mRNA (9). This presynaptic Y2 receptor has therefore been proposed to regulate the release of NPY (10, 11) and other colocalized neurotransmitters involved ...

Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice

“…D2 receptor RNA is elevated in L relative to V rats within the anterior pituitary [53], but to our knowledge, this is the first study to provide evidence that the D2 receptor expression is elevated within the CNS. Increases of NPY Y2 receptor in L females has not been reported, but would be consistent with the elevation of NPY signaling during lactation; NPY Y2 is the primary NPY receptor in the brain and is involved in feeding regulation [37]. However, other roles for NPY Y2 receptor in behaviors such as stress coping and anxiety [36,47], suggest the intriguing possibility that this receptor plays multiple roles during lactation.…”

Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects

“…NPY2R knock-outs have been shown to increase food intake, weight and adiposity [25]. Furthermore, in other mouse models, it has been observed that NPY2R regulates production of NPY, agouti-related peptide (AgRP), proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART), and these changes are associated with functional changes in food intake [50]. Abbott et al [51] have demonstrated that blockade of the NPY2R with a specific antagonist lowers the effect of endogenous and exogenous PYY 3-36 on food intake.…”

Common neuropeptide Y2 receptor gene variant is protective against obesity among Swedish men

“…7 Peripheral administration of PYY in rodents reduces NPY mRNA levels and increases the POMC mRNA levels in the arcuate nucleus, as well as reduces food intake, but has no effect in fasted Y2R knockout mice. 7,16 However, there are redundancy or compensatory mechanisms as reflected by slightly increased body weight and generally larger food intake in full, and conditional hypothalamic, Y2R knock-out mice 33,34 and by results from studies on other NPY receptor knockouts. 35 Hung et al 18 recently reported association for Y2R 585T4C polymorphism to obesity-related parameters among 421 men representing the general population in eastern UK.…”