Adult-onset PYY overexpression in mice reduces food intake and increases lipogenic capacity

Abstract

Peptide YY (PYY) is best known for its important role in appetite regulation, but recent pharmacological studies have suggested that PYY is also involved in regulating energy balance and glucose homeostasis. However, the mechanism behind the regulation of these parameters by PYY is less clear. Here, by utilising an inducible transgenic mouse model where PYY overexpression is induced in adult animals (PYYtg) and release of mature PYY peptides is controlled by endogenous machineries, we show that elevating PYY levels leads to reduced food intake after a 24-h fast. Furthermore, PYYtg mice, although not significantly different from WT with respect to body weight, adiposity, lean mass, physical activity or energy expenditure, exhibited a significantly increased respiratory exchange ratio (RER), indicating decreased lipid oxidation and/or increased lipogenesis. Importantly, PYYtg mice showed a 25% reduction in liver protein levels of phosphorylated acetyl-CoA carboxylase (pACC) in the absence of changes in total ACC levels compared to those of WT mice. Moreover, liver protein levels of AMP-activated kinase (AMPK) in PYYtg mice were 25% lower than those of WT mice, consistent with a reduced pACC in these mice. These data suggest that elevation of PYY levels as seen after a meal can increase lipogenic capacity, which is likely a key contributor to the increased RER seen in PYYtg mice. In addition, PYYtg mice exhibited comparable insulin tolerance and oral glucose tolerance to those of WT, but showed a trend towards decreased insulin levels in response to an oral glucose challenge, indicating that PYY could improve insulin action. Taken together, these findings demonstrate that under physiological conditions, PYY reduces food intake while enhancing lipogenic capacity and insulin action, likely contributing to fuel assimilation in the postprandial state.

Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression

“…Notably, in our previous study, the single-housed mice fed WPI had a reduced intestinal length and reduced ileal gene expression for PYY and FATP4 (26), whereas group-housed mice used in the current study only reduced FATP4 gene expression. Given the (contrasting) effects of PYY on anabolic and catabolic pathways (43), and the role played by FATP4 in intestinal lipid transport (2), the data suggest a potential interaction between the housing environment and whey proteins on intestinal morphology (length) and cellular activity linked to energy balance regulation. In fact, Tranberg et al showed that group-housed mice fed WPI as part of a 60% energy high-fat diet (HFD) also increased energy intake and reduced body weight gain, similar to the current study, but, in this instance, the effect was transient, only seen in the first week of diet intake (47).…”

Y1 receptor deficiency in β-cells leads to increased adiposity and impaired glucose metabolism

“…Importantly, PYY and PP levels are known to increase in response to food intake and they can act as satiety factors on specific Y-receptors in the brain 13,16,17,54,55 . A local increase in PYY or PP in the pancreatic islet would therefore also be very timely to counter-regulate the increase of insulin secretion postprandial.…”

“…Additionally, adrenaline, noradrenaline and peptide YY (PYY) have also been implicated in the inhibition of insulin release 11–15 . PYY, a 36 amino acid peptide released from L-type cells of the gut and a member of the NPY family, is well recognised for its role to inhibit feeding and increase energy expenditure through activation of hypothalamic Y-receptors 13,16,17 . Importantly, however, PYY is also expressed in α-cells in the pancreatic islets where it is co-stored with glucagon in the secretory granules 18,19 , and its function in this tissue is less clear.…”

“…It is well established that central as well as peripheral actions of the NPY system are involved in the regulation of energy balance, with central pathways mostly promoting feeding via the activation of central Y1 receptors. In contrast, circulating PYY and its processed form PYY3–36, can both act on Y2 receptors located in brain areas with a semi-permeable blood brain barrier such as the arcuate nucleus (Arc) of the hypothalamus to mediate satiety 16,22,23 . In addition to central nervous system, Y1 receptors are also expressed in peripheral tissues including the liver, muscle, adipose tissue and pancreas, suggesting a potential role of the peripheral Y1 receptor signaling in regulating diverse physiological processes.…”

“…Indirect evidence from global Y1-deficient mice that exhibit hyperinsulinemia suggests a link between insulin secretion and Y1 receptor signaling in the islets in vivo 33 . However, the global deletion of Y1 receptors in mice leads to the development of obesity and impaired feeding 13,16,33 , and it remains therefore unclear as to whether hyperinsulinemia is the direct cause of Y1 receptor deficiency in the pancreas or the secondary effect of obesity.…”