Involvement of Neuropeptide Y in Hyperphagia in Human Growth Hormone Transgenic Rats

Abstract

ABSTRACT. We have previously produced human growth hormone (hGH) transgenic (TG) rats that show low circulating levels of both hGH and endogenous rat GH. Although body length of the TG rats is normal, they develop hyperphagia and severe obesity. The present study was undertaken to elucidate the causes of hyperphagia in the TG rats by focusing on temporal changes in plasma ghrelin levels and hypothalamic neuropeptide Y (NPY) contents. In both wild-type (WT) and TG rats, the highest value of plasma ghrelin levels was observed just before the dark phase, and thereafter plasma ghrelin levels were maintained higher in the TG than WT rats. Although NPY contents also showed the peak level just before the dark phase in both the arcuate (ARC) and paraventricular nuclei (PVN) of the hypothalamus, the values in the ARC, but not the PVN, of the TG rats was always lower than those of the WT rats, suggesting increased transport of NPY from the ARC to PVN in the TG rats. In addition, treatment with antagonists for Y1 and Y5 receptors for NPY reduced food intake much more effectively in the TG than WT rats. Intermittent treatment with recombinant hGH for a week significantly decreased food consumption, adipose tissue weight and plasma triglyceride concentrations in the TG rats. These results suggest that, in the TG rats, insufficiency in circulating GH stimulates the ghrelin-NPY system with a resultant increase in food intake. KEY WORDS: ghrelin, growth hormone, hyperphagia, neuropeptide Y, transgenic rat.J. Vet. Med. Sci. 68(9): 959-965, 2006 Growth hormone (GH) is secreted from the pituitary gland in a pulsatile manner and plays an important role in regulating metabolism as well as somatic growth [8,10]. The actions of GH on metabolism involve both anabolism, such as protein synthesis in the muscle, and catabolism, such as lipolysis in the adipose tissue. Therefore, the role of GH is very important in terms of maintaining the balance of body composition. Indeed, GH-deficient (GHD) subjects become obesity with short stature and this obesity in GHD subjects is improved by GH-replacement therapy [9,29]. Since the subjects of Prader-Willi syndrome (PWS), a type of GHD, typically represent hyperphagia [14], GH may also be involved in maintaining normal feeding.We have previously generated transgenic (TG) rats expressing human GH (hGH) gene under the control of mouse whey acidic protein promoter [18]. Contrary to our expectation, serum hGH levels in the TG rats were relatively low and endogenous pulsatile secretion of rat GH was eliminated. While their body length was similar to that of the wild-type (WT) rats, the TG rats developed severe obesity [15] and hyperphagia [12], suggesting that they suffered from GHD. Additionally, the TG rats showed several symptoms that are linked to non-insulin dependent diabetes mellitus, e.g. hyperglycemia, hyperinsulinemia, and hypertriglyceridemia [16]. The TG rats, therefore, appear to be a good experimental model for the study of hyperphagia and resulting obesity and metabolic diseases under...

Free Access to Running Wheels Abolishes Hyperphagia in Human Growth Hormone Transgenic Rats

“…* P <0.05 vs. RW (−) by a Student’s t test.). As reported previously [5,6,7, 9, 11], body weight gain in TG rats was higher than that in WT rats without running wheel access after 14 weeks of age ( P <0.0167, by a Student’s t test and a Bonferroni correction). Running wheel access resulted in decreased body weight gain in both WT and TG rats.…”

“…Otsuka Long-Evans Tokushima fatty (OLETF) rats, lacking cholecystokinin receptors, showed temporal decrease of food consumption only in the initial period of wheel access [1], while Zucker fatty rats, which have a leptin receptor missense mutation, did not change their food consumption throughout the experiment [22]. In TG rats, leptin resistance [6], high peripheral ghrelin levels and increased transport of neuropeptide Y (NPY) from the arcuate nucleus (ARC) to paraventricular nucleus (PVN) of the hypothalamus [9] are suspected as the causation of the hyperphagia. Therefore, the different outcomes observed as to the effect of running wheel on food consumption may be attributable to the different causes of hyperphagia.…”

“…The TG rats exhibit unique serum growth hormone (GH) phenotype; serum hGH concentrations are relatively low, while their endogenous pulsatile rat GH secretion was almost completely suppressed [12]. The TG rats show significant hyperphagia from their young stage [5, 6, 9] and severe obesity [5,6,7, 9, 11], while their body length was almost normal [11, 12]. It is widely accepted that GH has effects on metabolism of carbohydrate and lipid, such as increasing glucose output of liver or increasing free fatty acid levels.…”

The Role of “Mixed” Orexigenic and Anorexigenic Signals and Autoantibodies Reacting with Appetite-Regulating Neuropeptides and Peptides of the Adipose Tissue-Gut-Brain Axis: Relevance to Food Intake and Nutritional Status in Patients with Anorexia Nervosa and Bulimia Nervosa

“…Recently, studies in rodents suggested a possible mediation of ghrelin action on GH by NPY and that GH may be involved in maintaining feeding [68]. Plasma ghrelin levels are elevated during fasting and suppressed after meal.…”