Article

PYY transgenic mice are protected against diet-induced and genetic obesity

Neuroscience Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia.
Neuropeptides (Impact Factor: 2.55). 03/2008; 42(1):19-30. DOI: 10.1016/j.npep.2007.11.003
Source: PubMed

ABSTRACT The gut-derived hormone, peptide YY (PYY) reduces food intake and enhances satiety in both humans and animals. Obese individuals also have a deficiency in circulating peptide YY, although whether this is a cause or a consequence of obesity is unclear. Our aims were to determine whether peptide YY (PYY) over-expression may have therapeutic effects for the treatment of obesity by altering energy balance and glucose homeostasis. We generated PYY transgenic mice and measured body weight, food intake, temperature, adiposity, glucose tolerance, circulating hormone and lipid concentrations and hypothalamic neuropeptide levels (neuropeptide Y; proopiomelanocortin, and thyrotropin-releasing hormone) under chow and high-fat feeding and after crossing these mice onto the genetically obese leptin-deficient ob/ob mouse background. PYY transgenic mice were protected against diet-induced obesity in association with increased body temperature (indicative of increased thermogenesis) and sustained expression of thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus. Moreover, PYY transgenic mice crossed onto the genetically obese ob/ob background had significantly decreased weight gain and adiposity, reduced serum triglyceride levels and improved glucose tolerance compared to ob/ob controls. There was no effect of PYY transgenic over expression on basal or fasting-induced food intake measured at 11-12 weeks of age. Together, these findings suggest that long-term administration of PYY, PYY-like compounds or agents that stimulate PYY synthesis in vivo can reduce excess adiposity and improve glucose tolerance, possibly via effects on the hypothalamo-pituitary-thyroid axis and thermogenesis.

0 Bookmarks
 · 
131 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The gastrointestinal hormone peptide tyrosine tyrosine 3-36 (PYY3-36) has attained broad recognition with respect to its involvement in energy homeostasis and the control of food intake. It is mainly secreted by distal intestinal enteroendocrine L-cells in response to eating and exerts both neurally mediated paracrine and endocrine effects on various target organs. In addition to its gastrointestinal effects, PYY3-36 has long been known to inhibit food intake. Recent closer examination of the effects of PYY3-36 revealed that this gut-derived peptide also influences a wide spectrum of behavioral and cognitive functions that are pivotal for basic processes of perception and judgment, including central information processing, salience learning, working memory, and behavioral responding to novelty. Here, we review the effects of PYY3-36 that go beyond food intake and provide a conceptual framework suggesting that several apparently unrelated behavioral actions of PYY3-36 may actually reflect different manifestations of modulating the central dopamine system. Copyright © 2014. Published by Elsevier Inc.
    Frontiers in Neuroendocrinology 12/2014; DOI:10.1016/j.yfrne.2014.12.003 · 7.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases.
    Metabolism 08/2014; DOI:10.1016/j.metabol.2014.08.004 · 3.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:Contrasting with obesity, constitutional thinness (CT) is a rare condition of natural low bodyweight. CT exhibits preserved menstruation in females, no biological marker of undernutrition, no eating disorders but a bodyweight gain desire. Anorexigenic hormonal profile with high peptide tyrosine tyrosine (PYY) was shown in circadian profile. CT could be considered as the opposite of obesity, where some patients appear to resist diet-induced bodyweight loss.Objective:The objective of this study was to evaluate appetite regulatory hormones in CTs in an inverse paradigm of diet-induced weight loss.Methods:A 4-week fat overfeeding (2640 kJ excess) was performed to compare eight CT women (body mass index (BMI)<17.5 kg m(-)(2)) to eight female controls (BMI 18.5-25 kg m(-)(2)). Appetite regulatory hormones profile after test meal, food intake, bodyweight, body composition, energy expenditure and urine metabolomics profiles were monitored before and after overfeeding.Results:After overfeeding, fasting total and acylated ghrelin were significantly lower in CTs than in controls (P=0.01 and 0.03, respectively). After overfeeding, peptide tyrosine tyrosine (PYY) and glucagon-like-peptide 1 both presented earlier (T15 min vs T30 min) and higher post-meal responses (incremental area under the curve) in CTs compared with controls. CTs failed to increase bodyweight (+0.22±0.18 kg, P=0.26 vs baseline), contrasting with controls (+0.72±0.26 kg, P=0.03 vs baseline, P=0.01 vs CTs). Resting energy expenditure increased in CTs only (P=0.031 vs baseline). After overfeeding, a significant negative difference between total energy expenditure and food intake was noticed in CTs only (-2754±720 kJ, P=0.01).Conclusion:CTs showed specific adaptation to fat overfeeding: overall increase in anorexigenic hormonal profile, enhanced post prandial GLP-1 and PYY and inverse to controls changes in urine metabolomics. Overfeeding revealed a paradoxical positive energy balance contemporary to a lack of bodyweight gain, suggesting yet unknown specific energy expenditure pathways in CTs.
    Nutrition & Diabetes 07/2014; 4:e126. DOI:10.1038/nutd.2014.17 · 1.52 Impact Factor