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.
- SourceAvailable from: Dileep N Lobo[show abstract] [hide abstract]
ABSTRACT: PURPOSE OF REVIEW: To highlight recent developments relating control of food intake after surgery and the gut-brain axis by reviewing clinically relevant English language articles mainly from January 2011 to March 2013. RECENT FINDINGS: The gut-brain axis involves a number of complex interactions between hypothalamic nuclei and the gastrointestinal tract. In the postoperative period, release of cytokines and neuromodulators are involved in the control of food intake. Analogues of neuromodulators have been developed and tested in animal studies. The emerging field of metabolic surgery has allowed study of these mechanisms in greater detail. SUMMARY: The current epidemic of worldwide obesity demands further research into the mechanisms underlying control of food intake.Current opinion in clinical nutrition and metabolic care. 06/2013;
- [show abstract] [hide abstract]
ABSTRACT: Gastrointestinal peptides are increasingly being linked to processes controlling the maintenance of bone mass. Peptide YY (PYY), a gut-derived satiety peptide of the neuropeptide Y family, is upregulated in some states that also display low bone mass. Importantly, PYY has high affinity for Y-receptors, particularly Y1R and Y2R, which are known to regulate bone mass. Anorexic conditions and bariatric surgery for obesity influence circulating levels of PYY and have a negative impact on bone mass, but the precise mechanism behind this is unclear. We thus examined whether alterations in PYY expression affect bone mass. Bone microstructure and cellular activity were analyzed in germline PYY knockout and conditional adult-onset PYY over-expressing mice at lumbar and femoral sites using histomorphometry and micro-computed tomography. PYY displayed a negative relationship with osteoblast activity. Male and female PYY knockout mice showed enhanced osteoblast activity, with greater cancellous bone mass. Conversely, PYY over-expression lowered osteoblast activity in vivo, via a direct Y1 receptor mediated mechanism involving MAPK stimulation evident in vitro. In contrast to PYY knockout mice, PYY over expression also altered bone resorption, as indicated by greater osteoclast surface, despite the lack of Y-receptor expression in osteoclastic cells. While evident in both sexes, cellular changes were generally more pronounced in females. These data demonstrate that the gut peptide PYY is critical for the control of bone remodeling. This regulatory axis from the intestine to bone has the potential to contribute to the marked bone loss observed in situations of extreme weight loss and higher circulating PYY levels, such as anorexia and bariatric obesity surgery, and may be important in the maintenance of bone mass in the general population.PLoS ONE 01/2012; 7(7):e40038. · 3.73 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Objective: PYY3-36 and PP potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. Design and Methods: Fasted WT, Y2(-/-) , Y4(-/-) or Y2Y4(-/-) mice were i.p. administrated with saline, PYY3-36 and/or PP. Results: We demonstrate that combined injection of PYY3-36 and PP reduces food intake in an additive manner. This effect is mediated via Y2 and Y4 receptors, respectively. We demonstrate that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the Arc, PVN and DMH are activated with minimal responses seen in the VMH and LHA of WT mice. These effects are absent in Y2(-/-) mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. Conclusions: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.Obesity 06/2013; · 3.92 Impact Factor