Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

Abstract

Objective: Neuropeptide Y and its Y receptors are important players in the regulation of energy homeostasis. However, while their functions in feeding regulation are well recognized, functions in other critical aspects of energy homeostasis are largely unknown. To investigate the function of Y1 receptors in the regulation of energy homeostasis, we examined energy expenditure, physical activity, body composition, oxidative fuel selection and mitochondrial oxidative capacity in germline Y1 À/À mice as well as in a conditional Y1-receptor-knockdown model in which Y1 receptors were knocked down in peripheral tissues of adult mice. Results: Germline Y1À/À mice of both genders not only exhibit a decreased respiratory exchange ratio, indicative of increased lipid oxidation, but interestingly also develop late-onset obesity. However, the increased lipid oxidation is a primary effect of Y1 deletion rather than secondary to increased adiposity, as young Y1 À/À mice are lean and show the same effect. The mechanism behind this is likely because of increased liver and muscle protein levels of carnitine palmitoyltransferase-1 (CPT-1) and maximal activity of key enzymes involved in b-oxidation; b-hydroxyacyl CoA dehydrogenase (bHAD) and medium-chain acyl-CoA dehydrogenase (MCAD), leading to increased mitochondrial capacity for fatty acid transport and oxidation. These effects are controlled by peripheral Y1-receptor signalling, as adult-onset conditional Y1 knockdown in peripheral tissues also leads to increased lipid oxidation, liver CPT-1 levels and bHAD activity. Importantly, these mice are resistant to diet-induced obesity. Conclusions: This work shows the primary function of peripheral Y1 receptors in the regulation of oxidative fuel selection and adiposity, opening up new avenues for anti-obesity treatments by targeting energy utilization in peripheral tissues rather than suppressing appetite by central effects.

Neuropeptide Y Y1 receptor antagonism increases bone mass in mice

“…BIBO3304 had no si there was a trend to (p = 0.06). This redu significant difference mice over this 8-wee Both germline and shown to strongly infl accretion [10,26]. Afte were observed betw mice with respect to rimetry (Table 4).…”

“…4B). Both germline and peripheral-specific Y1 receptor deletion has been shown to strongly influence energy homeostasis, thermogenesis and fat accretion [10,26]. After 4-weeks of treatment, no significant differences were observed between vehicle-and higher dose BIBO3304-treated mice with respect to metabolic parameters analysed by indirect calorimetry (Table 4).…”

“…The average was used for statistical analysis. Indirect calorimetry Metabolic rate was measured by indirect calorimetry using an eight-chamber open-circuit calorimeter (Oxymax Series; Columbus Instruments, Columbus, OH, USA) as described previously [10]. Briefly, pre-weighed mice were housed individually in specially built Plexiglas cages (20.1 × 10.1 × 12.7 cm).…”

“…NPY is a neurotransmitter widely expressed through the peripheral and central nervous system, and its actions are mediated through the activation of G-protein coupled receptors, namely Y1, Y2, Y4, Y5 and y6 receptors [9]. Through specific activation of the Y1 receptor, NPY has been shown to play a critical role in a number of centrally-regulated physiological functions, such as energy homeostasis [10], anxiety [11], cardiovascular function [12] and neurogenesis [13]. More recently, NPY has been shown to regulate bone homeostasis via actions in peripheral tissues.…”

“…In order to avoid stress induced by gavage or transcutaneous delivery, BIBO3304 was incorporated into an artificially flavoured jelly [23] and given to mice that had been trained to eat it on a daily basis for 8 weeks. Due to the wide distribution of Y1 receptors in peripheral tissues [24] and the Y1 receptor-mediated actions in other physiological systems such as energy homeostasis [10], metabolic changes were also monitored throughout the treatment period. butyl]-α-phenyl-benzeneacetamide ditrifluoroacetate (Tocris Bioscience, Bristol, UK) was delivered orally to mice via a novel method previously described [23].…”